Inhibitors of glucocorticoid receptor

ABSTRACT

The present invention relates generally to compositions and methods for treating cancer and hypercortisolism. Provided herein are substituted steroidal derivative compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibition of glucocorticoid receptors. Furthermore, the subject compounds and compositions are useful for the treatment of cancer and hypercortisolism.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 U.S. National Stage Entry of InternationalApplication No. PCT/US2016/068435, filed Dec. 22, 2016, which claims thebenefit of U.S. Application Ser. No. 62/387,253, filed Dec. 23, 2015,each of which are hereby incorporated by reference in their entirety.

BACKGROUND

A need exists in the art for an effective treatment of cancer,neoplastic disease, and hypercortisolism.

BRIEF SUMMARY OF THE INVENTION

Provided herein are substituted steroidal derivative compounds andpharmaceutical compositions comprising said compounds. The subjectcompounds and compositions are useful as inhibitors of glucocorticoidreceptors (GR). Furthermore, the subject compounds and compositions areuseful for the treatment of cancer, such as prostate cancer, breastcancer, lung cancer, and ovarian cancer, and hypercortisolism.

Some embodiments provided herein describe compounds having the structureof Formula (I), or a pharmaceutically acceptable salt, solvate, orprodrug thereof:

wherein

-   R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkyNR³S(O)₂R⁶,    -alkyNR³S(O)₂NR³R⁴, —NR³S(O)R⁶, —NR³aralkyl, —Oaralkyl, —C(O)NR³R⁴,    —OC(O)OR⁵, —C(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, or    —SR⁶;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, —S(O)₂R⁶, —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted heteroalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,    —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments,

-   R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkyNR³S(O)₂R⁶,    -alkyNR³S(O)₂NR³R⁴, —NR³aralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, or    —S(O)₂R⁶;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    fluoroalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —C(O)N(R¹⁰)₂,    or —S(O)₂R⁶;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 3-, 4-, 5-, or 6-membered heterocycle;-   R⁵ is optionally substituted alkyl, fluoroalkyl, optionally    substituted carbocyclyl, or optionally substituted heterocyclyl;-   R⁶ is optionally substituted alkyl, fluoroalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    fluoroalkyl, halo, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, optionally    substituted carbocyclyl, or optionally substituted carbocyclylalkyl;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted 3-, 4-, 5-, or        6-membered ring containing 0-2 heteroatoms selected from the        group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments, R¹ is —NR³S(O)₂R⁶, —NR³aralkyl, —C(O)NR³R⁴,—S(O)₂NR³R⁴, or —S(O)₂R⁶. In certain embodiments, R¹ is —NR³S(O)₂R⁶ or—S(O)₂NR³R⁴. In some embodiments, R³ and R⁴ are each independently —H,optionally substituted alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,—C(O)N(R¹⁰)₂, or —S(O)₂R⁶. In certain embodiments, R³ and R⁴ are eachindependently —H, alkyl, or —S(O)₂R⁶. In other embodiments, R³ and R⁴attached to the same N atom are taken together with the N atom to whichthey are attached to form a substituted or unsubstituted 4-, 5-, or6-membered ring heterocycle containing 0-3 heteroatoms selected from—O—, —NH—, —NR⁵—, —S—, and —S(O)₂—; and R⁵ is alkyl. In someembodiments, R⁶ is alkyl, carbocyclyl, optionally substituted aryl,optionally substituted aralkyl, or optionally substituted heterocyclyl.In some embodiments, R⁶ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl, optionallysubstituted phenyl, optionally substituted benzyl, or optionallysubstituted heterocyclyl. In some embodiments, R⁷ and R⁸ are eachindependently —H, alkyl, or carbocyclyl. In certain embodiments, R⁷ andR⁸ are —H.

Also provided herein, in some embodiments, are prodrugs of a compound ofFormula (I), having the structure of Formula (Id):

wherein R⁹ is —X—Y; X is a bond or —C(O); and Y is optionallysubstituted alkyl.

Other embodiments provided herein describe compounds having thestructure of Formula (II), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   R¹ is optionally substituted C₂₋₁₀ alkyl, optionally substituted    C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, C₁₋₁₀ bromoalkyl, C₁₋₁₀    chloroalkyl, optionally substituted hydroxyalkyl, optionally    substituted alkylheteroalkyl, optionally substituted alkyNMe₂,    optionally substituted alkylNH₂, optionally substituted alkylNHMe,    optionally substituted alkylNR³R⁴, —NR³R⁴, optionally substituted    carbocyclyl, optionally substituted heterocyclyl, —C(O)R⁵, —OH, —CN,    —CO₂H, or —NO₂;-   R³ and R⁴ are each independently —H, optionally substituted C₂₋₁₀    alkyl, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,    —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments,

-   R¹ is optionally substituted C₂₋₁₀ alkyl, optionally substituted    C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, optionally substituted    hydroxyalkyl, optionally substituted alkylheteroalkyl, optionally    substituted alkylNMe₂, optionally substituted alkylNH₂, optionally    substituted alkylNHMe, optionally substituted alkylNR³R⁴, —NR³R⁴,    optionally substituted carbocyclyl, optionally substituted    heterocyclyl, or —C(O)R⁵;-   R³ and R⁴ are each independently —H, optionally substituted C₂₋₁₀    alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 3-, 4-, 5-, or 6-membered heterocycle;-   R⁵ is alkyl, fluoroalkyl, carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁶ is alkyl, fluoroalkyl, carbocyclyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heterocyclyl,    or optionally substituted heteroaryl; and-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    fluoroalkyl, halo, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, optionally    substituted carbocyclyl, or optionally substituted carbocyclylalkyl;-   or R⁷ and R⁸ are taken together with the atom to which they are    attached to form a substituted or unsubstituted 3-, 4-, 5-, or    6-membered ring containing 0-2 heteroatoms selected from the group    consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments, R¹ is C₂₋₁₀ alkyl, C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl,hydroxyalkyl, alkylheteroalkyl, alkylNMe₂, alkylNH₂, alkylNHMe,alkylNR³R⁴, —NR³R⁴, carbocyclyl, heterocyclyl, or —C(O)R⁵. In certainembodiments, R¹ is C₂₋₁₀ alkyl, hydroxyalkyl, or alkylalkoxy. In furtherembodiments, R¹ is carbocyclyl, heterocyclyl, or —C(O)R⁵. In someembodiments, R⁵ is alkyl, carbocyclyl, or heterocyclyl; and R⁶ is alkyl,carbocyclyl, aralkyl, or heterocyclyl. In some embodiments, R⁷ and R⁸are each independently —H, alkyl, or carbocyclyl. In certainembodiments, R⁷ and R⁸ are —H.

Also provided herein, in some embodiments, are compounds having thestructure of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,    —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or    —NO₂;-   each R² is —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,    —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or    —NO₂;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,    —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—;-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 1, 2, 3, or 4;-   wherein if R¹ is H, then n=2, 3, or 4; if R¹ is OMe and R⁷ and R⁸    are H, then R² is not Me, OMe, or F; if R¹ is OH and R⁷ and R⁸ are    H, then R² is not Me; if R¹ is NHMe, n is 1, and R⁷ and R⁸ are H,    then R² is not F; and if R¹ is Cl, n is 1, and R⁷ and R are H, then    R² is not CF₃.

In some embodiments, R is —H, —NR³R⁴, optionally substituted alkylNR³R⁴,halo, —OR⁵, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —C(O)R⁵, —C(O)NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In certainembodiments, R¹ is —H, —NR³R⁴, alkylNR³R⁴, halo, —OR⁵, alkyl,fluoroalkyl, carbocyclyl, heterocyclyl, or —CN. In further embodiments,R¹ is —NR³R⁴, halo, —OR⁵, alkyl, or heterocyclyl. In other embodiments,R is —NMe₂, —NHMe, —NH₂, methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, iso-propoxy,morpholino, or pyrrolidino. In some embodiments, each R² is —NR³R⁴,halo, —OR⁵, alkyl, carbocyclyl, alkoxy, or —CN. In some embodiments, R³and R⁴ are alkyl. In some embodiments, R³ and R⁴ attached to the same Natom are taken together with the N atom to which they are attached toform a 4-, 5- or 6-membered heterocycle containing 0 or 1 oxygenheteroatom. In certain embodiments, R⁵ is alkyl. In some embodiments, R⁷and R⁸ are each independently —H, alkyl, or carbocyclyl. In certainembodiments, R⁷ and R⁸ are —H. In certain embodiments, n is 1. In otherembodiments, n is 2.

Also provided herein, in some embodiments, are prodrugs of a compound ofFormula (III), having the structure of Formula (IIIo):

wherein R⁹ is —X—Y; X is a bond or —C(O); and Y is optionallysubstituted alkyl.

Some embodiments provided herein describe a pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a compound ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

Also provided herein are methods for treating or preventing cancer in asubject, the method comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. Also provided herein aremethods for reducing incidences of cancer recurrence, the methodcomprising administering to a subject in cancer remission atherapeutically effective amount of a compound having the structure ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. Some embodiments providedherein describe methods for treating a chemo-resistant cancer in asubject, the method comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula (I), Formula (II), or Formula (III), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In some embodiments, the cancer is triple negative breast cancer, highgrade serous ovarian cancer, castration resistant prostate cancer, ordoubly resistant prostate cancer. In some embodiments, the cancer isnon-small cell lung cancer. In some embodiments, the methods furthercomprise administering a second therapeutic agent to the subject. Insome embodiments, the methods further comprise administering one or moreadditional therapeutic agents. In some embodiments, the second oradditional therapeutic agent is an androgen receptor signalinginhibitor. In specific embodiments, the androgen receptor signalinginhibitor is 3,3′-diindolylmethane (DIM), abiraterone acetate, ARN-509,bexlosteride, bicalutamide, dutasteride, epristeride, enzalutamide,finasteride, flutamide, izonsteride, ketoconazole,N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidalantiandrogens, turosteride, or any combinations thereof. In someembodiments, the second or additional therapeutic agent is achemotherapeutic agent. In other embodiments, the second or additionaltherapeutic agent is cisplatin, carboplatin, paclitaxel, gemcitabine,doxorubicin, camptothecin, topotecan, or any combinations thereof. Insome embodiments, the second or additional therapeutic agent is animmunotherapy agent (e.g., an anti-PD-L1 agent or an anti-PD1 agent). Incertain embodiments, the second or additional therapeutic agent is ananti-PD-L1 agent. In certain embodiments, the second or additionaltherapeutic agent is an anti-PD1 agent.

Other embodiments provided herein describe methods for treating ahypercortisolism disease or disorder in a subject, the method comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound having the structure of Formula (I), Formula (II),or Formula (III), or a pharmaceutically acceptable salt, solvate, orprodrug thereof. In certain embodiments, the hypercortisolism disease ordisorder is Cushing's syndrome. In certain embodiments, thehypercortisolism disease or disorder is refractory Cushing's syndrome.

In some embodiments of Formula (III):

-   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,    —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —CN, —CO₂H, or —NO₂;-   R² is —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵, —OH,    optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,    —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —CN, —CO₂H, or —NO₂;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—; and-   n is 1, 2, 3, or 4; wherein if R¹ is H, then n=2, 3, or 4.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference for the specificpurposes identified herein.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof known to those skilled in the art, and so forth.When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange, in some instances, will vary between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) is not intendedto exclude that in other certain embodiments, for example, an embodimentof any composition of matter, composition, method, or process, or thelike, described herein, “consist of” or “consist essentially of” thedescribed features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl). In other embodiments, analkyl comprises one to two carbon atoms (e.g., C₁-C₂ alkyl). In otherembodiments, an alkyl comprises one carbon atom (e.g., C₁ alkyl). Inother embodiments, an alkyl comprises five to fifteen carbon atoms(e.g., C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five toeight carbon atoms (e.g., C₅-C₈alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises three to five carbon atoms (e.g., C₃-C₅alkyl). In other embodiments, the alkyl group is selected from methyl,ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl(n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl isattached to the rest of the molecule by a single bond. Unless statedotherwise specifically in the specification, an alkyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O— alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl comprises two to four carbonatoms. The alkynyl is attached to the rest of the molecule by a singlebond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, andthe like. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group isthrough one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. In certainembodiments, an alkynylene comprises two to eight carbon atoms (e.g.,C₂-C₈ alkynylene). In other embodiments, an alkynylene comprises two tofive carbon atoms (e.g., C₂-C₅ alkynylene). In other embodiments, analkynylene comprises two to four carbon atoms (e.g., C₂-C₄ alkynylene).In other embodiments, an alkynylene comprises two to three carbon atoms(e.g., C₂-C₃ alkynylene). In other embodiments, an alkynylene comprisestwo carbon atom (e.g., C₂ alkylene). In other embodiments, an alkynylenecomprises five to eight carbon atoms (e.g., C₅-C₈ alkynylene). In otherembodiments, an alkynylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkynylene). Unless stated otherwise specifically in thespecification, an alkynylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula —O—R^(c)-aryl where R^(c) is an alkylene chain as defined above,for example, methylene, ethylene, and the like. The alkylene chain partof the aralkyl radical is optionally substituted as described above foran alkylene chain. The aryl part of the aralkyl radical is optionallysubstituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is saturated (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unlessotherwise stated specifically in the specification, the term“carbocyclyl” is meant to include carbocyclyl radicals that areoptionally substituted by one or more substituents independentlyselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula —R^(c)-carbocyclylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the carbocyclyl radical is optionally substituted as defined above.

“Carbocyclylalkynyl” refers to a radical of the formula—R^(c)-carbocyclyl where R^(c) is an alkynylene chain as defined above.The alkynylene chain and the carbocyclyl radical is optionallysubstituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkylene chain asdefined above. The alkylene chain and the carbocyclyl radical isoptionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, trichloromethyl, dichloromethyl,chloromethyl, 2,2,2-trichloroethyl, 1-chloromethyl-2-chloroethyl,tribromomethyl, dibromomethyl, bromomethyl, 2,2,2-tribromoethyl,1-bromomethyl-2-bromoethyl, and the like. In some embodiments, the alkylpart of the haloalkyl radical is optionally substituted as defined abovefor an alkyl group.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Insome embodiments, the alkyl part of the fluoroalkyl radical isoptionally substituted as defined above for an alkyl group.

“Heteroalkyl” refers to an alkyl group in which one or more skeletalatoms of the alkyl are selected from an atom other than carbon, e.g.,oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl. Unless stated otherwise specifically in thespecification, an heteroalkyl chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical that comprises two to twelve carbon atoms and from one to sixheteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocyclyl radical isa monocyclic, bicyclic, tricyclic or tetracyclic ring system, whichoptionally includes fused or bridged ring systems. The heteroatoms inthe heterocyclyl radical are optionally oxidized. One or more nitrogenatoms, if present, are optionally quaternized. The heterocyclyl radicalis partially or fully saturated. The heterocyclyl is attached to therest of the molecule through any atom of the ring(s). Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include,but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include,but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl,2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formula—R^(c)-heterocyclyl where R^(c) is an alkylene chain as defined above.If the heterocyclyl is a nitrogen-containing heterocyclyl, theheterocyclyl is optionally attached to the alkyl radical at the nitrogenatom. The alkylene chain of the heterocyclylalkyl radical is optionallysubstituted as defined above for an alkylene chain. The heterocyclylpart of the heterocyclylalkyl radical is optionally substituted asdefined above for a heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula —O—R^(c)-heterocyclyl where R^(c) is an alkylene chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkylene chain of theheterocyclylalkoxy radical is optionally substituted as defined abovefor an alkylene chain. The heterocyclyl part of the heterocyclylalkoxyradical is optionally substituted as defined above for a heterocyclylgroup.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

The compounds disclosed herein, in some embodiments, contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)—. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentinvention, whether radioactive or not, are encompassed within the scopeof the present invention. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in vivo half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Scheme and Examples hereinusing appropriate isotopically-enriched reagents and/or intermediates.In some embodiments, the compounds described herein contain one or moreisotopic variants (e.g., deuterium, tritium, ¹³C, and/or ¹⁴C).

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein, in certain embodiments, exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the substitutedsteroidal derivative compounds described herein is intended to encompassany and all pharmaceutically suitable salt forms. Preferredpharmaceutically acceptable salts of the compounds described herein arepharmaceutically acceptable acid addition salts and pharmaceuticallyacceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and. aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are, in some embodiments, prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the saltaccording to methods and techniques with which a skilled artisan isfamiliar.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Pharmaceutically acceptable base addition salts are, insome embodiments, formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating,” or “palliating” or“ameliorating” are used interchangeably. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are, in some embodiments,administered to a patient at risk of developing a particular disease, orto a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease has not been made.

“Prodrug” is meant to indicate a compound that is, in some embodiments,converted under physiological conditions or by solvolysis to abiologically active compound described herein. Thus, the term “prodrug”refers to a precursor of a biologically active compound that ispharmaceutically acceptable. A prodrug is typically inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis. The prodrug compound often offersadvantages of solubility, tissue compatibility or delayed release in amammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985),pp. 7-9, 21-24 (Elsevier, Amsterdam).

Abbreviations used herein have their conventional meaning within thechemical and biological arts. The following abbreviations have theindicated meaning throughout: Na₂HPO₄=disodium phosphate, AcOH=aceticacid, aq.=aqueous, NH4Cl=ammonium chloride, DCM=dichloromethane,DMPU=1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,ESI=electrospray ionization, EtOAc=ethyl acetate, g=gram, h=hour,LCMS=liquid chromatography mass spectrometry, LDA=lithiumdiisopropylamide, MgSO₄=magnesium sulfate, m/s=mass-to-charge ratio,mg=milligram, MeOH=methanol, min=minute, NMR=nuclear magnetic resonance,RT or rt=room temperature, sat.=saturated, NaHCO₃=sodium bicarbonate,NaBH₄=sodium borohydride, Na₂CO₃=sodium carbonate, NaCl=sodium chloride,Na₂SO₄=sodium sulfate, Na₂S₂O₃=sodium thiosulfate, TFA=trifluoroaceticacid, and THF=tetrahydrofuran.

Substituted Steroidal Derivative Compounds

Substituted steroidal derivative compounds are described herein that areGR inhibitors. These compounds, and compositions comprising thesecompounds, are useful for the treatment of cancer, neoplastic disease,and hypercortisolism diseases and disorders.

Some embodiments provided herein describe a compound having thestructure of Formula (I), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   -   R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkylNR³S(O)₂R⁶,        -alkylNR³S(O)₂NR³R⁴, —NR³S(O)R⁶, —NR³aralkyl, —C(O)NR³R⁴,        —OC(O)OR⁵, —C(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,        —S(O)R⁶, or —SR⁶;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted aryl, optionally substituted        heterocyclyl, optionally substituted heterocyclylalkyl,        optionally substituted heteroaryl, —S(O)₂R⁶, —C(O)N(R¹⁰)₂,        —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   R⁵ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted heteroalkyl,        optionally substituted aryl, optionally substituted aralkyl,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   R⁷ and R⁸ are each independently —H, optionally substituted        alkyl, haloalkyl, halo, optionally substituted carbocyclyl,        optionally substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted heterocyclyl, optionally        substituted heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴,        —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl.

In some embodiments,

-   R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkyNR³S(O)₂R⁶,    -alkyNR³S(O)₂NR³R⁴, —NR³aralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, or    —S(O)₂R⁶;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    fluoroalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —C(O)N(R¹⁰)₂    or —S(O)₂R⁶;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 3-, 4-, 5-, or 6-membered heterocycle;-   R⁵ is optionally substituted alkyl, fluoroalkyl, optionally    substituted carbocyclyl, or optionally substituted heterocyclyl;-   R⁶ is optionally substituted alkyl, fluoroalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    fluoroalkyl, optionally substituted carbocyclyl, or optionally    substituted carbocyclylalkyl;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted 3-, 4-, 5-, or        6-membered ring containing 0-2 heteroatoms selected from the        group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments,

-   R¹ is —NR³S(O)₂R⁶, —NR³aralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, or    —S(O)₂R⁶;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    fluoroalkyl, or optionally substituted carbocyclyl;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 3-, 4-, 5-, or 6-membered heterocycle optionally        containing an oxygen or sulfur atom;    -   wherein if R³ or R⁴ is substituted, R³ or R⁴ is substituted with        alkyl, halo, hydroxy, alkoxy, or fluoroalkyl;-   R⁶ is optionally substituted alkyl, optionally substituted    carbocyclyl, or optionally substituted aryl; and-   wherein if R⁶ is substituted, R⁶ is substituted with alkyl or halo;-   R⁷ and R⁸ are each independently —H, optionally alkyl, carbocyclyl,    or carbocyclylalkyl;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a 3-, 4-, 5-, or 6-membered carbocyclyl.

For any and all of the embodiments of Formula (I), substituents areselected from among a subset of the listed alternatives.

In some embodiments, R¹ is —NR³S(O)₂R⁶, —NR³aralkyl, —Oaralkyl,—C(O)NR³R⁴, —C(O)OR⁵, —S(O)₂NR³R⁴, —NR³S(O)₂NR³R⁴, or —S(O)₂R⁶. In someembodiments, R¹ is —NR³S(O)₂R⁶ or —NR³S(O)₂NR³R⁴. In some embodiments,R¹ is -alkylNR³S(O)₂R⁶ or -alkylNR³S(O)₂NR³R⁴. In some embodiments, R¹is —NR³S(O)₂R⁶,—S(O)₂NR³R⁴ or —S(O)₂R⁶. In some embodiments, R¹ is—C(O)OR⁵ or —C(O)NR³R⁴. In some embodiments, R¹ is —NR³aralkyl or—Oaralkyl. In some embodiments, R¹ is —NR³S(O)₂R⁶. In some embodiments,R¹ is —S(O)₂NR³R⁴. In some embodiments, R¹ is —S(O)₂R⁶.

In some embodiments, R³ and R⁴ are each independently —H, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, —C(O)N(R¹⁰)₂, or—S(O)₂R⁶. In some embodiments, R³ and R⁴ are each independently —H,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl,—C(O)N(R¹⁰)₂, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are eachindependently —H, C₁₋₆alkyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴are each independently —H, methyl, ethyl, propyl, iso-propyl, butyl,sec-butyl, iso-butyl, tert-butyl, or —S(O)₂R⁶. In some embodiments, R³and R⁴ are each independently —H, methyl, or —S(O)₂R⁶. In certainembodiments, R³ and R⁴ are each independently —H or —C(O)N(R¹⁰)₂.

In other embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-5-, or 6-membered ring heterocyclecontaining 0-3 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocyclecontaining 1 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5-, or 6-membered ring heterocycle containing 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form a 4-, 5-, or6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, R³ and R⁴ are optionally substituted with halo,alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R³ and R⁴are optionally substituted with fluoro or C₁₋₆alkyl. In someembodiments, R³ and R⁴ are optionally substituted with fluoro or methyl.

In some embodiments, R⁵ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl. In some embodiments, R⁵ is C₁₋₆alkyl, C₁₋₆fluoroalkyl,C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In certain embodiments, R⁵ isC₁₋₆alkyl. In certain embodiments, R⁵ is methyl, ethyl, propyl,iso-propyl, butyl, sec-butyl, iso-butyl, or tert-butyl.

In some embodiments, R⁶ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁶ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁶is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁶ is optionally substituted benzyl.In some embodiments, R⁶ is C₃₋₆carbocyclyl. In some embodiments, R⁶ isphenyl. In some embodiments, R⁶ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁶ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent.

In certain embodiments, R⁶ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R⁶ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁶ isoptionally substituted with fluoro or methyl.

In some embodiments, R⁷ and R⁸ are each independently —H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₆carbocyclyl, C₁₋₆alkyl C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, C₁₋₆alkylC₃₋₆heterocyclyl, —OH, —OR⁵,—NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵ or R⁷and R⁸ are taken together with the atom to which they are attached toform a ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R⁸ and R⁹ are each independently —H, C₁₋₆alkyl, or C₃₋₆carbocyclyl,methoxy, ethoxy, propoxy, iso-propoxy, —NH₂, —NMe₂, —NHMe, —NEt₂,—C(O)NH₂, —C(O)NMe₂, —C(O)NHMe, or —CN. In some embodiments, R⁷ and R⁸are each independently —H, C₁₋₆alkyl, C₁₋₆fluoroalkyl, orC₃₋₆carbocyclyl. In some embodiments, R⁷ and R⁸ are each independently—H, C₁₋₆alkyl, or C₃₋₆carbocyclyl. In some embodiments, R⁷ is —H and Ris C₁₋₆alkyl, C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl. In some embodiments,R⁷ is —H and R⁸ is alkyl. In some embodiments, R⁷ is C₁₋₆alkyl,C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl and R is —H. In some embodiments, R⁷is methyl and R⁸ is —H. In some embodiments, R⁷ and R⁸ are —H. In someembodiments, R⁷ and R⁸ are C₁₋₆alkyl. In some embodiments, R⁷ and R⁸ aremethyl.

In other embodiments, R⁷ and R⁸ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁷ and R⁸ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocycle ring.

In some embodiments, each R¹⁰ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹⁰ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹⁰ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹⁰ is independentlyalkyl or aryl. In some embodiments, each R¹⁰ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹⁰ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹⁰ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹⁰ is independently hydrogen ormethyl.

In some embodiments, compounds described herein have the followingstructure of Formula (Ia):

In some embodiments, compounds described herein have the followingstructure of Formula (Ib):

In some embodiments, compounds described herein have the followingstructure of Formula (Ic):

In some embodiments, compounds described herein have the followingstructure of Formula (Ie):

Some embodiments provided herein describe a prodrug of a compound ofFormula (I) having the structure of Formula (Id):

wherein

-   -   R⁹ is —X—Y;        -   X is a bond or —C(O); and        -   Y is optionally substituted alkyl.

In some embodiments, X is a bond. In other embodiments, X is —C(O). Incertain embodiments, Y is C₁₋₁₀alkyl.

Other embodiments provided herein describe a compound having thestructure of Formula (II), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   -   R¹ is optionally substituted alkyl, optionally substituted        alkoxy, fluoroalkyl, bromoalkyl, chloroalkyl, optionally        substituted hydroxyalkyl, optionally substituted        alkylheteroalkyl, optionally substituted alkylNMe₂, optionally        substituted alkylNH₂, optionally substituted alkylNHMe,        optionally substituted alkylNR³R⁴, —NR³R⁴, optionally        substituted carbocyclyl, optionally substituted heterocyclyl,        —C(O)R⁵, —OH, —CN, —CO₂H, or —NO₂;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted carbocyclylalkyl, optionally substituted aryl,        optionally substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,        —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   R⁵ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   R⁷ and R⁸ are each independently —H, optionally substituted        alkyl, haloalkyl, halo, optionally substituted carbocyclyl,        optionally substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted heterocyclyl, optionally        substituted heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴,        —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl.

In some embodiments,

-   R¹ is optionally substituted C₂₋₁₀ alkyl, optionally substituted    C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, C₁₋₁₀ bromoalkyl, C₁₋₁₀    chloroalkyl, optionally substituted hydroxyalkyl, optionally    substituted alkylheteroalkyl, optionally substituted alkylNMe₂,    optionally substituted alkylNH₂, optionally substituted alkylNHMe,    optionally substituted alkylNR³R⁴, —NR³R⁴, optionally substituted    carbocyclyl, optionally substituted heterocyclyl, —C(O)R⁵, —OH, —CN,    —CO₂H, or —NO₂;-   R³ and R⁴ are each independently —H, optionally substituted C₂₋₁₀    alkyl, haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,    —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—; and-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl.

In some embodiments,

-   R¹ is C₂₋₁₀ alkyl, C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, hydroxyalkyl,    alkylheteroalkyl, C₁₋₆ alkylNMe₂, C₁₋₆ alkylNH₂, C₁₋₆ alkylNHMe,    C₁₋₆ alkylNR³R⁴, —NR³R⁴, optionally substituted carbocyclyl,    optionally substituted heterocyclyl, or —C(O)R⁵;-   R³ and R⁴ are each independently —H, optionally substituted C₂₋₁₀    alkyl, fluoroalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, or —S(O)₂R⁶;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted 3-, 4-, 5-, or 6-membered heterocycle;-   R⁵ is alkyl, fluoroalkyl, carbocyclyl, optionally substituted aryl,    optionally substituted heterocyclyl, or optionally substituted    heteroaryl;-   R⁶ is alkyl, fluoroalkyl, carbocyclyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heterocyclyl,    or optionally substituted heteroaryl; and-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    fluoroalkyl, halo, optionally substituted carbocyclyl, or optionally    substituted carbocyclylalkyl;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted 3-, 4-, 5-, or        6-membered ring containing 0-2 heteroatoms selected from the        group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—.

In some embodiments,

-   R¹ is C₂₋₁₀ alkyl, C₂₋₆ alkoxy, C₂₋₆ fluoroalkyl, C₁₋₆ hydroxyalkyl,    C₁₋₆ alkylheteroC₁₋₆ alkyl, or C₃₋₆ carbocyclyl; and-   R⁷ and R⁸ are each independently —H, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl,    or C₃₋₆ carbocyclyl;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a 3-, 4-, 5-, or 6-membered carbocycle.

For any and all of the embodiments of Formula (II), substituents areselected from among a subset of the listed alternatives.

In some embodiments, R¹ is optionally substituted C₂₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, optionallysubstituted hydroxyalkyl, optionally substituted alkylheteroalkyl,optionally substituted alkylNMe₂, optionally substituted alkylNH₂,optionally substituted alkylNHMe, optionally substituted alkylNR³R⁴,—NR³R⁴, optionally substituted carbocyclyl, optionally substitutedheterocyclyl, —C(O)R⁵, —OH, —CN, —CO₂H, or —NO₂. In some embodiments, R¹is C₂₋₁₀ alkyl, C₂₋₁₀ alkoxy, C₂₋₁₀ fluoroalkyl, hydroxyalkyl,alkylheteroalkyl, alkylNMe₂, alkylNH₂, alkylNHMe, alkylNR³R⁴,—NR³R⁴,carbocyclyl, heterocyclyl, or —C(O)R⁵. In some embodiments, R¹ is C₃₋₈alkyl, C₂₋₁₀ alkoxy, C₁₋₆ hydroxyalkyl, C₁₋₆ alkylheteroC₁₋₆ alkyl,C₁₋₆alkylNMe₂, C₁₋₆alkylNH₂, C₁₋₆alkylNHMe, C₁₋₆alkylNR³R⁴, —NR³R⁴,C₃₋₆carbocyclyl, C₃₋₆heterocyclyl, or —C(O)R⁵. In some embodiments, R¹is C₁₋₆alkylNMe₂, C₁₋₆alkylNH₂, C₁₋₆alkylNHMe, C₁₋₆alkylNR³R⁴, —NR³R⁴.In some embodiments, R¹ is alkylNMe₂, alkylNH₂, or alkylNHMe. In someembodiments, R¹ is —NR³R⁴. In some embodiments, R¹ is alkylNR³R⁴. Insome embodiments, R¹ is C₃₋₆ alkyl. In some embodiments, R¹ is C₂₋₁₀alkoxy, C₁₋₆ hydroxyalkyl, or C₁₋₆ alkylheteroC₁₋₆ alkyl. In someembodiments, R¹ is C₂₋₁₀ alkyl, hydroxyalkyl, or alkylalkoxy. In someembodiments, R¹ is carbocyclyl, heterocyclyl, or —C(O)R⁵. In someembodiments, R¹ is C₃₋₆carbocyclyl. In some embodiments, R¹ isC₃₋₆heterocyclyl. In some embodiments, R¹ is —C(O)R⁵.

In certain embodiments, R¹ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R¹ isoptionally substituted with fluoro or methyl.

In some embodiments, R³ and R⁴ are each independently —H, C₂₋₆ alkyl,C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl, C₂₋₆heterocyclyl, C₁₋₆ alkyC₃₋₆heterocyclyl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶. Insome embodiments, R³ and R⁴ are each independently —H, C₂₋₆alkyl,C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl, or —S(O)₂R⁶. In someembodiments, R³ and R⁴ are each independently —H, C₂₋₆alkyl,—C(O)N(R¹⁰)₂, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are eachindependently —H, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ areeach independently —H. In certain embodiments, R³ and R⁴ are eachindependently —H or —C(O)N(R¹⁰)₂.

In other embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocyclecontaining 0-3 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocyclecontaining 1 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5-, or 6-membered ring heterocycle containing 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form a 4-, 5-, or6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, R³ and R⁴ are optionally substituted with halo,alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R³ and R⁴are optionally substituted with fluoro or C₁₋₆alkyl. In someembodiments, R³ and R⁴ are optionally substituted with fluoro or methyl.

In some embodiments, R⁵ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl. In some embodiments, R⁵ is alkyl, carbocyclyl, orheterocyclyl. In some embodiments, R is C₁₋₆alkyl, C₁₋₆fluoroalkyl,C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In certain embodiments, R⁵ isC₁₋₆alkyl. In certain embodiments, R⁵ is methyl, ethyl, propyl,iso-propyl, butyl, sec-butyl, iso-butyl, or tert-butyl.

In some embodiments, R⁶ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁶ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁶is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁶ is optionally substituted benzyl.In some embodiments, R⁶ is C₃₋₆carbocyclyl. In some embodiments, R⁶ isphenyl. In some embodiments, R⁶ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁶ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent. In some embodiments, R⁶ isalkyl, carbocyclyl, aralkyl, or heterocyclyl

In certain embodiments, R⁶ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluroralkyl. In some embodiments, R⁶ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁶ isoptionally substituted with fluoro or methyl.

In some embodiments, R⁷ and R⁸ are each independently —H, C₁₋₆alkyl,C₁₋₆haloalkyl, halo, C₃₋₆carbocyclyl, C₁₋₆alkyl C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, C₁₋₆alkylC₃₋₆heterocyclyl, —OH,—S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵ or R⁷ and R⁸ are taken togetherwith the atom to which they are attached to form a ring containing 0-2heteroatoms selected from the group consisting of —O—, —NH—, —NR⁶—, —S—,and —S(O)₂—. In some embodiments, R⁷ and R⁸ are each independently —H,C₁₋₆alkyl, halo, C₃₋₆carbocyclyl, methoxy, ethoxy, propoxy, iso-propoxy,—NH₂, —NMe₂, —NHMe, —NEt₂, —C(O)NH₂, —C(O)NMe₂, —C(O)NHMe, or —CN. Insome embodiments, R⁷ and R⁸ are each independently —H, C₁₋₆alkyl,C₁₋₆fluoroalkyl, halo, or C₃₋₆carbocyclyl. In some embodiments, R⁷ andR⁸ are each independently —H, C₁₋₆alkyl, or C₃₋₆carbocyclyl. In someembodiments, R⁷ is —H and R is C₁₋₆alkyl, C₁₋₆fluoroalkyl, orC₃₋₆carbocyclyl. In some embodiments, R⁷ is —H and R⁸ is alkyl. In someembodiments, R⁷ is C₁₋₆alkyl, C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl and Ris —H. In some embodiments, R⁷ is methyl and R⁸ is —H. In someembodiments, R⁷ and R⁸ are —H. In some embodiments, R⁷ and R⁸ areC₁₋₆alkyl. In some embodiments, R⁷ and R⁸ are methyl.

In other embodiments, R⁷ and R⁸ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁷ and R⁸ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocycle ring.

In some embodiments, each R¹⁰ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹⁰ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹⁰ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹⁰ is independentlyalkyl or aryl. In some embodiments, each R¹⁰ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹⁰ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹⁰ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹⁰ is independently hydrogen ormethyl. In some embodiments, R¹⁰ is H. In other embodiments, R¹⁰ isalkyl. In other embodiments, R¹⁰ is aryl.

In some embodiments, compounds described herein have the followingstructure of Formula (IIa):

In some embodiments, compounds described herein have the followingstructure of Formula (IIb):

In some embodiments, compounds described herein have the followingstructure of Formula (IIc):

Other embodiments provided herein describe a compound having thestructure of Formula (III), or a pharmaceutically acceptable salt,solvate, or prodrug thereof:

wherein

-   -   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,        —OH, optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted hydroxyalkyl, —C(O)R⁵,        —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,        —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂;    -   each R² is independently —NR³R⁴, optionally substituted        alkylNR³R⁴, halo, —OR⁵, —OH, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted heterocyclyl, optionally        substituted heterocyclylalkyl, optionally substituted        hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵,        —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶,        —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted carbocyclylalkyl, optionally substituted aryl,        optionally substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,        —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   R⁵ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   R⁷ and R⁸ are each independently —H, optionally substituted        alkyl, haloalkyl, halo, optionally substituted carbocyclyl,        optionally substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted heterocyclyl, optionally        substituted heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴,        —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—;    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl; and    -   n is 1, 2, 3, or 4;    -   wherein if R¹ is H, then n=2, 3, or 4.

In some embodiments, if R is OMe and R⁷ and R⁸ are H, then R² is not Me,OMe, or F. In some embodiments, if R is OH and R⁷ and R⁸ are H, then R²is not Me. In some embodiments, if R¹ is NHMe, n is 1, and R⁷ and R⁸ areH, then R² is not F. In some embodiments, if R¹ is Cl, n is 1, and R⁷and R⁸ are H, then R² is not CF₃.

In some embodiments, if R¹ is —OR⁵, then each R² is independently—NR³R⁴, optionally substituted alkylNR³R⁴, Br, Cl, optionallysubstituted C₂₋₁₀ alkoxy, —OH, optionally substituted C₂₋₁₀ alkyl,fluoroalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted hydroxyalkyl,—C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,—S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂. In someembodiments, if R¹ is —OR⁵, then each R² is independently —NR³R⁴,alkylNR³R⁴, C₂₋₁₀ alkyl, fluoroalkyl, carbocyclyl, or —CN. In someembodiments, if R¹ is —OR⁵, then R⁷ or R⁸ is not H. In some embodiments,if R¹ is —OR⁵, then R⁷ or R is alkyl or carbocyclyl. In someembodiments, if R¹ is OMe, then each R² is independently —NR³R⁴,optionally substituted alkylNR³R⁴, Br, Cl, optionally substituted C₂₋₁₀alkoxy, —OH, optionally substituted C₂₋₁₀ alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted hydroxyalkyl, —C(O)R⁵,—C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,—S(O)R⁶, —SR⁶, —CN, —CO₂H, or —NO₂. In some embodiments, if R¹ is OMe,then R⁷ or R⁸ is not H. In some embodiments, if R¹ is OMe, then R⁷ or R⁸is alkyl or carbocyclyl.

In some embodiments, if R¹ is —OH, then each R² is independently —NR³R⁴,optionally substituted alkylNR³R⁴, halo, —OR⁵, —OH, optionallysubstituted C₂₋₁₀ alkyl, fluoroalkyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted hydroxyalkyl,—C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,—S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂. In someembodiments, if R¹ is —OH, then each R² is independently —NR³R⁴,optionally substituted alkylNR³R⁴, halo, —OR⁵, —OH, fluoroalkyl,optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴,—OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —CN,—CO₂H, or —NO₂. In some embodiments, if R¹ is —OH, then each R² isindependently —NR³R⁴, alkylNR³R⁴, halo, fluoroalkyl, carbocyclyl, or—CN. In some embodiments, if R is —OH, then then R⁷ or R is not H. Insome embodiments, if R is —OH, then R⁷ or R is alkyl or carbocyclyl.

In other embodiments, if R¹ is —NHMe, then each R² is independently—NR³R⁴, optionally substituted alkylNR³R⁴, Br, Cl, —OR⁵, —OH, optionallysubstituted alkyl, fluoroalkyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheteroalkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted hydroxyalkyl, —C(O)R⁵,—C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,—S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂. In otherembodiments, if R¹ is —NHMe, then each R² is independently —NR³R⁴,optionally substituted alkylNR³R⁴, —OR⁵, —OH, optionally substitutedalkyl, fluoroalkyl, optionally substituted carbocyclyl, optionallysubstituted carbocyclylalkyl, optionally substituted heteroalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted hydroxyalkyl, —C(O)R⁵,—C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,—S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂. In otherembodiments, if R¹ is —NHMe, then each R² is independently —NR³R⁴,alkylNR³R⁴, —OR⁵, —OH, alkyl, fluoroalkyl, carbocyclyl, or —CN. In someembodiments, if R¹ is —NHMe, then n is 2, 3, or 4. In some embodiments,if R¹ is —NHMe, then then R⁷ or R⁸ is not H. In some embodiments, if R¹is —NHMe, then R⁷ or R⁸ is alkyl or carbocyclyl.

In some embodiments, if R¹ is halo, then each R² is independently—NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵, —OH, alkyl,optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴,—OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶,—NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂. In some embodiments, if R¹ is halo,then each R² is independently —NR³R⁴, alkyNR³R⁴, halo, —OR⁵, —OH, alkyl,carbocyclyl, or —CN. In other embodiments, if R¹ is halo, then n is 2,3, or 4. In some embodiments, if R¹ is halo, then R⁷ or R⁸ is not H. Insome embodiments, if R¹ is halo, then R⁷ or R⁸ is alkyl or carbocyclyl.In some embodiments, if R¹ is Cl, then each R² is independently —NR³R⁴,optionally substituted alkylNR³R⁴, halo, —OR⁵, —OH, alkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedhydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or—NO₂. In some embodiments, if R¹ is Cl, then each R² is independently—NR³R⁴, alkylNR³R⁴, halo, —OR⁵, —OH, alkyl, carbocyclyl, or —CN. Inother embodiments, if R¹ is Cl, then n is 2, 3, or 4. In someembodiments, if R¹ is Cl, then R⁷ or R⁸ is not H. In some embodiments,if R¹ is Cl, then R⁷ or R⁸ is alkyl or carbocyclyl.

In some embodiments,

-   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,    —OH, optionally substituted alkyl, haloalkyl, optionally substituted    carbocyclyl, optionally substituted carbocyclylalkyl, optionally    substituted heteroalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴,    —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or    —NO₂;-   each R² is independently —NR³R⁴, optionally substituted alkylNR³R⁴,    halo, —OR⁵, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵,    —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴,    —CN, —CO₂H, or —NO₂;-   R³ and R⁴ are each independently —H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ is optionally substituted alkyl, haloalkyl, halo, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, —OH, —OR⁵,    —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;-   R⁸ is —H, optionally substituted alkyl, haloalkyl, halo, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, —OH, —OR⁵,    —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—;-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 1, 2, 3, or 4;-   wherein if R¹ is H, then n=2, 3, or 4.

In some embodiments,

-   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, —F, optionally    substituted alkyl, haloalkyl, optionally substituted carbocyclyl,    optionally substituted carbocyclylalkyl, optionally substituted    heteroalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted hydroxyalkyl,    —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,    —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂;-   each R² is independently —NR³R⁴, optionally substituted alkylNR³R⁴,    halo, —OR⁵, —OH, optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted carbocyclylalkyl,    optionally substituted heteroalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵,    —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴,    —CN, —CO₂H, or —NO₂;-   R³ and R⁴ are each independently optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted aryl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,    —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;    -   or R³ and R⁴ attached to the same N atom are taken together with        the N atom to which they are attached to form a substituted or        unsubstituted heterocycle;-   R⁵ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted heterocyclyl, or optionally substituted heteroaryl;-   R⁶ is optionally substituted alkyl, haloalkyl, optionally    substituted carbocyclyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl;-   R⁷ and R⁸ are each independently —H, optionally substituted alkyl,    haloalkyl, halo, optionally substituted carbocyclyl, optionally    substituted carbocyclylalkyl, optionally substituted heteroalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,    —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   or R⁷ and R⁸ are taken together with the atom to which they are        attached to form a substituted or unsubstituted ring containing        0-2 heteroatoms selected from the group consisting of —O—, —NH—,        —NR⁶—, —S—, and —S(O)₂—;-   each R¹⁰ is independently H, optionally substituted alkyl,    haloalkyl, optionally substituted carbocyclyl, optionally    substituted heteroalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted heterocyclyl, or    optionally substituted heteroaryl; and-   n is 1, 2, 3, or 4;-   wherein if R¹ is H, then n=2, 3, or 4.

For any and all of the embodiments of Formula (III), substituents areselected from among a subset of the listed alternatives.

In some embodiments, R¹ is —H, —NR³R⁴, optionally substituted alkyNR³R⁴,halo, —OR⁵, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —C(O)R⁵, —C(O)NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In someembodiments, R¹ is —H, —NR³R⁴, alkylNR³R⁴, halo, —OR⁵, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, —C(O)R⁵, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,—NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In some embodiments, R¹ is —H, —NR³R⁴,C₁₋₆alkylNR³R⁴, halo, —OR⁵, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl. In some embodiments, R¹ is—S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In someembodiments, R¹ is —H, —NR³R⁴, alkyNR³R⁴, halo, —OR⁵, alkyl,fluoroalkyl, carbocyclyl, heterocyclyl, or —CN. In other embodiments, R¹is —NMe₂, —NHMe, —NH₂, methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, methoxy ethoxy, propoxy, iso-propoxy,morpholino, or pyrrolidino. In some embodiments, R¹ is —NR³R⁴, halo,—OR⁵, alkyl, or heterocyclyl. In some embodiments, R¹ is —H, —NR³R⁴,halo, —OR⁵, or alkyl. In some embodiments, R¹ is —H. In someembodiments, R¹ is —NR³R⁴. In some embodiments, R¹ is —NMe₂. In someembodiments, R¹ is —NHMe. In some embodiments, R¹ is —NH₂. In someembodiments, R¹ is —NMeEt. In some embodiments, R¹ is —NEt₂. In someembodiments, R¹ is -halo. In some embodiments, R¹ is fluoro. In someembodiments, R¹ is chloro. In some embodiments, R¹ is —OR. In someembodiments, R¹ is methoxy. In some embodiments, R¹ is ethoxy. In someembodiments, R¹ is propoxy. In some embodiments, R¹ is iso-propoxy. Insome embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆alkyl. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl. Insome embodiments, R¹ is propyl. In some embodiments, R¹ is iso-propyl.In some embodiments, R¹ is C₃₋₆carbocyclyl. In some embodiments, R¹ iscyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R¹ isazetadino, morpholino, thiomorpholino, piperidino, piperazino, orpyrrolidino. In some embodiments, R¹ is morpholino. In some embodiments,R¹ is pyrrolidino. In some embodiments, R¹ is azetadino.

In certain embodiments, R¹ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R¹ isoptionally substituted with fluoro or methyl.

In some embodiments, each R² is independently —NR³R⁴, optionallysubstituted alkylNR³R⁴, halo, —OR⁵, —OH, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted hydroxyalkyl, —C(O)R⁵, —C(O)NR³R⁴, —S(O)₂NR³R⁴,—S(O)₂R⁶, —NR³S(O)₂NR³R⁴, or —CN. In some embodiments, each R² isindependently —NR³R⁴, alkylNR³R⁴, halo, —OR⁵, —OH, alkyl, haloalkyl,carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, hydroxyalkyl, —C(O)R⁵, —C(O)NR³R⁴, —S(O)₂NR³R⁴,—S(O)₂R⁶, —NR³S(O)₂NR³R⁴, or —CN. In some embodiments, each R² isindependently —NR³R⁴, C₁₋₆alkylNR³R⁴, halo, —OR⁵, —OH, C₁₋₆alkyl,C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₁₋₆alkylC₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, C₁₋₆alkylC₃₋₆heterocyclyl,C₁₋₆hydroxyalkyl, or —CN. In some embodiments, each R² is independently—C(O)R⁵, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, or —CN. Insome embodiments, each R² is independently —NR³R⁴, halo, —OR⁵,C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₁₋₆heteroalkyl,C₃₋₆heterocyclyl, or —CN. In some embodiments, each R² is independently—NR³R⁴, halo, alkyl, carbocyclyl, alkoxy, or —CN. In some embodiments,each R² is independently methyl, methoxy, ethyl, propyl, iso-propyl,cyclopropyl, fluoro, chloro, or —NMe₂. In some embodiments, each R² isindependently methyl, methoxy, iso-propyl, cyclopropyl, fluoro, chloro,or —NMe₂. In some embodiments, R² is methoxy. In some embodiments, R² ismethyl. In some embodiments R² is ethyl. In some embodiments, R² isiso-propyl. In some embodiments, R² is propyl. In some embodiments, R²is cyclopropyl. In some embodiments, R² is cyclobutyl. In someembodiments, R² is fluoro. In some embodiments, R² is chloro. In someembodiments, R² is —NMe₂. In some embodiments, R² is —NH₂. In someembodiments, R² is —NHMe. In some embodiments, R² is —NMeEt.

In certain embodiments, each R² is independently optionally substitutedwith halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In some embodiments,each R² is independently optionally substituted with fluoro orC₁₋₆alkyl. In some embodiments, each R² is independently optionallysubstituted with fluoro or methyl.

In some embodiments, R³ and R⁴ are each independently —H, C₁₋₆ alkyl,C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl, C₂₋₆heterocyclyl, C₁₋₆ alkylC₃₋₆heterocyclyl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶. Insome embodiments, R³ and R⁴ are each independently —H, C₁₋₆alkyl,C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl, —C(O)N(R¹⁰)₂, or—S(O)₂R⁶. In some embodiments, R³ and R⁴ are each independently —H,C₁₋₆alkyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are—H. In some embodiments, R³ and R⁴ are methyl.

In other embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-5-, or 6-membered ring heterocyclecontaining 0-3 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In some embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5- or 6-membered heterocycle containing 0 or 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocyclecontaining 1 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5-, or 6-membered ring heterocycle containing 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form a 4-, 5-, or6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, R³ and R⁴ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R³ and R⁴ are each independently optionally substitutedwith fluoro or C₁₋₆alkyl. In some embodiments, R³ and R⁴ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁵ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl. In some embodiments, R⁵ is alkyl, carbocyclyl, orheterocyclyl. In some embodiments, R⁵ is C₁₋₆alkyl, C₁₋₆fluoroalkyl,C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In certain embodiments, R⁵ isC₁₋₆alkyl. In certain embodiments, R⁵ is methyl, ethyl, propyl,iso-propyl, butyl, sec-butyl, iso-butyl, or tert-butyl.

In some embodiments, R⁶ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁶ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁶is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁶ is optionally substituted benzyl.In some embodiments, R⁶ is C₃₋₆carbocyclyl. In some embodiments, R⁶ isphenyl. In some embodiments, R⁶ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁶ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent. In some embodiments, R⁶ isalkyl, carbocyclyl, aralkyl, or heterocyclyl

In certain embodiments, R⁶ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluroralkyl. In some embodiments, R⁶ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁶ isoptionally substituted with fluoro or methyl.

In some embodiments, R⁷ and R⁸ are each independently —H, C₁₋₆alkyl,C₁₋₆haloalkyl, halo, C₃₋₆carbocyclyl, C₁₋₆alkyC₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl, C₁₋₆alkylC₃₋₆heterocyclyl, —OH, —OR⁵,—NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵ or R⁷and R⁸ are taken together with the atom to which they are attached toform a ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments,R⁷ and R are each independently —H, C₁₋₆alkyl, C₁₋₆fluoroalkyl, halo, orC₃₋₆carbocyclyl. In some embodiments, R⁷ and R⁸ are each independently—H, C₁₋₆alkyl, or C₃₋₆carbocyclyl. In some embodiments, R⁷ is —H and Ris C₁₋₆alkyl, C₁₋₆fluoroalkyl, halo, or C₃₋₆carbocyclyl. In someembodiments, R⁷ is —H and R⁸ is alkyl. In some embodiments, R⁷ isC₁₋₆alkyl, C₁₋₆fluoroalkyl, or C₃₋₆carbocyclyl and R is —H. In someembodiments, R⁷ is methyl and R⁸ is —H. In some embodiments, R⁷ and R⁸are —H. In some embodiments, R⁷ and R⁸ are C₁₋₆alkyl. In someembodiments, R⁷ and R⁸ are methyl.

In other embodiments, R⁷ and R⁸ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁷ and R⁸ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocycle ring.

In some embodiments, each R¹⁰ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹⁰ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹⁰ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹⁰ is independentlyalkyl or aryl. In some embodiments, each R¹⁰ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹⁰ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹⁰ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹⁰ is independently hydrogen ormethyl. In some embodiments, R¹ is H. In other embodiments, R¹⁰ isalkyl. In other embodiments, R¹⁰ is aryl.

In some embodiments, n is 1 or 2. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3 or 4.

In some embodiments, compounds described herein have the followingstructure of Formula (IIIa):

In some embodiments, compounds described herein have the followingstructure of Formula (IIb):

In some embodiments, compounds described herein have the followingstructure of Formula (IIc):

In some embodiments, compounds described herein have the followingstructure of Formula (IId):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIe):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIf):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIg):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIh):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIi):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIj):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIk):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIm):

In some embodiments, compounds described herein have the followingstructure of Formula (IIIn):

Some embodiments provided herein describe a prodrug of a compound ofFormula (III) having the structure of Formula (IIIo):

wherein

-   -   R⁹ is —X—Y;        -   X is a bond or —C(O); and        -   Y is optionally substituted alkyl.

In some embodiments, X is a bond. In other embodiments, X is —C(O). Incertain embodiments, Y is C₁₋₁₀alkyl.

Some embodiments provided herein describe a compound having thestructure of Formula (IV), or a pharmaceutically acceptable salt orprodrug thereof:

wherein

-   -   ring A is a heteroaryl, aryl, carbocyclyl, or heterocyclyl;    -   R¹ is —H, —NR³R⁴, alkylNR³R⁴, halo, —OR⁵, —OH, optionally        substituted alkyl, haloalkyl, optionally substituted        carbocyclyl, optionally substituted carbocyclylalkyl, optionally        substituted heteroalkyl, optionally substituted heterocyclyl,        optionally substituted heterocyclylalkyl, optionally substituted        hydroxyalkyl, —C(O)R⁵, —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵,        —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, —SR⁶,        —NR³S(O)₂NR³R⁴, —CN, —CO₂H, or —NO₂;    -   n is 0, 1, 2, 3, or 4;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted carbocyclylalkyl, optionally substituted aryl,        optionally substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted heteroaryl, —S(O)₂R⁶,        —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   R⁵ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted heterocyclyl, or optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   R⁷ and R⁸ are each independently —H, optionally substituted        alkyl, haloalkyl, halo, optionally substituted carbocyclyl,        optionally substituted carbocyclylalkyl, optionally substituted        heteroalkyl, optionally substituted heterocyclyl, optionally        substituted heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴,        —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—;    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl.

In some embodiments, ring A is a monocyclic heteroaryl, bicyclicheteroaryl, or naphthyl. In some embodiments, ring A is a bicyclicheteroaryl.

In some embodiments, a compound of formula (IV) has a structure of:

In other embodiments, ring A is a monocyclic heteroaryl. In someembodiments, ring A is pyridyl. In some embodiments, R¹ is alkyl or H.

In some embodiments, a compound of formula (IV) has a structure of:

Some embodiments provided herein describe a compound having thestructure of Formula (IV), wherein

-   -   ring A is a heteroaryl, aryl, carbocyclyl, or heterocyclyl;    -   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,        —OH, optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted hydroxyalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —C(O)OR⁵, —C(O)NR³R⁴, —OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,        —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —P(O)(OR⁵)₂,        —P(O)(R⁵)₂, —CN, —CO₂H, or —NO₂;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted aryl, optionally substituted heterocyclyl,        optionally substituted heteroaryl, —S(O)₂R⁶, —C(O)N(R¹⁰)₂,        —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   each R⁵ is independently optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted aryl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted heteroalkyl,        optionally substituted aryl, optionally substituted aralkyl,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   R⁷ is optionally substituted alkyl, haloalkyl, halo, optionally        substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,        —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   R⁸ is —H, optionally substituted alkyl, haloalkyl, halo,        optionally substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,        —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁵—, —S—, and —S(O)₂—;    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   and n is 0, 1, 2, 3, or 4.

Other embodiments provided herein describe a compound having thestructure of Formula (IV), wherein

-   -   ring A is a heteroaryl, aryl, carbocyclyl, or heterocyclyl;    -   R¹ is —H, —NR³R⁴, optionally substituted alkylNR³R⁴, halo, —OR⁵,        —OH, optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, optionally substituted hydroxyalkyl,        optionally substituted aryl, optionally substituted heteroaryl,        —C(O)OR⁵, —C(O)NR³R⁴,—OC(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴,        —S(O)₂R⁶, —S(O)R⁶, —SR⁶, —NR³S(O)₂NR³R⁴, —P(O)(OR⁵)₂,        —P(O)(R⁵)₂, —CN, —CO₂H, or —NO₂;    -   R³ and R⁴ are each independently —H, optionally substituted        alkyl, haloalkyl, optionally substituted carbocyclyl, optionally        substituted aryl, optionally substituted heterocyclyl,        optionally substituted heteroaryl, —S(O)₂R⁶, —C(O)N(R¹⁰)₂,        —C(O)R⁵, or —C(O)OR⁵;        -   or R³ and R⁴ attached to the same N atom are taken together            with the N atom to which they are attached to form a            substituted or unsubstituted heterocycle;    -   each R⁵ is independently optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted aryl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   R⁶ is optionally substituted alkyl, haloalkyl, optionally        substituted carbocyclyl, optionally substituted heteroalkyl,        optionally substituted aryl, optionally substituted aralkyl,        optionally substituted heterocyclyl, or optionally substituted        heteroaryl;    -   R⁷ is —H, optionally substituted alkyl, haloalkyl, halo,        optionally substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,        —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;    -   R⁸ is optionally substituted alkyl, haloalkyl, halo, optionally        substituted carbocyclyl, optionally substituted        carbocyclylalkyl, optionally substituted heteroalkyl, optionally        substituted heterocyclyl, optionally substituted        heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN, —S(O)₂R⁶,        —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵;        -   or R⁷ and R⁸ are taken together with the atom to which they            are attached to form a substituted or unsubstituted ring            containing 0-2 heteroatoms selected from the group            consisting of —O—, —NH—, —NR⁵—, —S—, and —S(O)₂—;    -   each R¹⁰ is independently H, optionally substituted alkyl,        haloalkyl, optionally substituted carbocyclyl, optionally        substituted heteroalkyl, optionally substituted aryl, optionally        substituted aralkyl, optionally substituted heterocyclyl, or        optionally substituted heteroaryl;    -   and n is 0, 1, 2, 3, or 4.

For any and all of the embodiments of Formula (IV), substituents areselected from among a subset of the listed alternatives.

In some embodiments, R¹ is —H, —NR³R⁴, optionally substituted alkyNR³R⁴,halo, —OR⁵, optionally substituted alkyl, fluoroalkyl, optionallysubstituted carbocyclyl, optionally substituted carbocyclylalkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, —C(O)R⁵, —C(O)NR³R⁴,—S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In someembodiments, R¹ is —H, —NR³R⁴, alkylNR³R⁴, halo, —OR⁵, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, —C(O)R⁵, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶,—NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In some embodiments, R¹ is —H, —NR³R⁴,C₁₋₆alkylNR³R⁴, halo, —OR⁵, C₁₋₆alkyl, C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl,C₁₋₆heteroalkyl, C₃₋₆heterocyclyl. In some embodiments, R¹ is—S(O)₂NR³R⁴, —S(O)₂R⁶, —NR³S(O)₂NR³R⁴, —CN, or —CO₂H. In someembodiments, R¹ is —H, —NR³R⁴, alkyNR³R⁴, halo, —OR⁵, alkyl,fluoroalkyl, carbocyclyl, heterocyclyl, or —CN. In other embodiments, R¹is —NMe₂, —NHMe, —NH₂, methyl, ethyl, propyl, iso-propyl, butyl,iso-butyl, sec-butyl, tert-butyl, methoxy ethoxy, propoxy, iso-propoxy,morpholino, or pyrrolidino. In some embodiments, R¹ is —NR³R⁴, halo,—OR⁵, alkyl, or heterocyclyl. In some embodiments, R¹ is —H, —NR³R⁴,halo, —OR⁵, or alkyl. In some embodiments, R¹ is —H. In someembodiments, R¹ is —NR³R⁴. In some embodiments, R¹ is —NMe₂. In someembodiments, R¹ is —NHMe. In some embodiments, R¹ is —NH₂. In someembodiments, R¹ is —NMeEt. In some embodiments, R¹ is —NEt₂. In someembodiments, R¹ is -halo. In some embodiments, R¹ is fluoro. In someembodiments, R¹ is chloro. In some embodiments, R¹ is —OR. In someembodiments, R¹ is methoxy. In some embodiments, R¹ is ethoxy. In someembodiments, R¹ is propoxy. In some embodiments, R¹ is iso-propoxy. Insome embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆alkyl. Insome embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl. Insome embodiments, R¹ is propyl. In some embodiments, R¹ is iso-propyl.In some embodiments, R¹ is C₃₋₆carbocyclyl. In some embodiments, R¹ iscyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R¹ isazetadino, morpholino, thiomorpholino, piperidino, piperazino, orpyrrolidino. In some embodiments, R¹ is morpholino. In some embodiments,R¹ is pyrrolidino. In some embodiments, R¹ is azetadino.

In certain embodiments, R¹ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluoroalkyl. In some embodiments, R¹ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R¹ isoptionally substituted with fluoro or methyl.

In some embodiments, R³ and R⁴ are each independently —H, C₁₋₆ alkyl,C₁₋₆ fluoroalkyl, C₃₋₆ carbocyclyl, C₁₋₆ carbocyclylalkyl, C₂₋₆heterocyclyl, C₁₋₆ alkyC₃₋₆heterocyclyl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶. Insome embodiments, R³ and R⁴ are each independently —H, C₁₋₆alkyl,C₁₋₆fluoroalkyl, C₃₋₆carbocyclyl, C₃₋₅heterocyclyl, —C(O)N(R¹⁰)₂, or—S(O)₂R⁶. In some embodiments, R³ and R⁴ are each independently —H,C₁₋₆alkyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are eachindependently —H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl,iso-butyl, tert-butyl, or —S(O)₂R⁶. In some embodiments, R³ and R⁴ are—H. In some embodiments, R³ and R⁴ are methyl.

In other embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-5-, or 6-membered ring heterocyclecontaining 0-3 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In some embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5- or 6-membered heterocycle containing 0 or 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form asubstituted or unsubstituted 4-, 5-, or 6-membered ring heterocyclecontaining 1 heteroatoms selected from —O—, —NH—, —NR⁵—, —S—, and—S(O)₂—. In other embodiments, R³ and R⁴ attached to the same N atom aretaken together with the N atom to which they are attached to form a 4-,5-, or 6-membered ring heterocycle containing 1 oxygen heteroatom. Inother embodiments, R³ and R⁴ attached to the same N atom are takentogether with the N atom to which they are attached to form a 4-, 5-, or6-membered ring. In some embodiments, the 4-, 5-, or 6-membered ring is

In certain embodiments, R³ and R⁴ are each independently optionallysubstituted with halo, alkyl, hydroxy, alkoxy, or fluoroalkyl. In someembodiments, R³ and R⁴ are each independently optionally substitutedwith fluoro or C₁₋₆alkyl. In some embodiments, R³ and R⁴ are eachindependently optionally substituted with fluoro or methyl.

In some embodiments, R⁵ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl. In some embodiments, R⁵ is alkyl, carbocyclyl, orheterocyclyl. In some embodiments, R⁵ is C₁₋₆alkyl, C₁₋₆fluoroalkyl,C₃₋₆carbocyclyl, or C₃₋₆heterocyclyl. In certain embodiments, R⁵ isC₁₋₆alkyl. In certain embodiments, R⁵ is methyl, ethyl, propyl,iso-propyl, butyl, sec-butyl, iso-butyl, or tert-butyl.

In some embodiments, R⁶ is alkyl, carbocyclyl, optionally substitutedaryl, optionally substituted aralkyl, or optionally substitutedheterocyclyl. In some embodiments, R⁶ is C₁₋₆alkyl, C₃₋₆carbocyclyl, oraryl optionally substituted with halo or alkyl. In some embodiments, R⁶is C₁₋₆alkyl, C₃₋₆carbocyclyl, or phenyl optionally substituted withhalo or alkyl. In some embodiments, R⁶ is optionally substituted benzyl.In some embodiments, R⁶ is C₃₋₆carbocyclyl. In some embodiments, R⁶ isphenyl. In some embodiments, R⁶ is phenyl substituted with 1-4 C₁₋₆alkylor fluoro substituents. In some embodiments, R⁶ is phenyl substitutedwith a C₁₋₆alkyl or fluoro substituent. In some embodiments, R⁶ isalkyl, carbocyclyl, aralkyl, or heterocyclyl

In certain embodiments, R⁶ is optionally substituted with halo, alkyl,hydroxy, alkoxy, or fluroralkyl. In some embodiments, R⁶ is optionallysubstituted with fluoro or C₁₋₆alkyl. In some embodiments, R⁶ isoptionally substituted with fluoro or methyl.

In some embodiments, R⁷ is —H and R is C₁₋₆alkyl, C₁₋₆haloalkyl, halo,C₃₋₆carbocyclyl, C₁₋₆alkylC₃₋₆carbocyclyl, C₁₋₆heteroalkyl,C₃₋₆heterocyclyl, C₁₋₆alkyC₃₋₆heterocyclyl, —OH, —OR⁵, —NR³R⁴,—C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵ or R⁷ and R⁸are taken together with the atom to which they are attached to form aring containing 0-2 heteroatoms selected from the group consisting of—O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁷ is —H and R⁸is C₁₋₆alkyl, C₁₋₆fluoroalkyl, halo, or C₃₋₆carbocyclyl. In someembodiments, R⁷ is —H and R⁸ is C₁₋₆alkyl, or C₃₋₆carbocyclyl. In someembodiments, R⁷ is —H and R⁸ is alkyl. In some embodiments, R⁷ is —H andR⁸ is methyl. In some embodiments, R⁷ is —H and R⁸ is ethyl.

In some embodiments, R⁸ is —H and R⁷ is C₁₋₆alkyl, C₁₋₆haloalkyl, halo,C₃₋₆carbocyclyl, C₁₋₆alkylC₃₋₆carbocyclyl, C₁₋₆heteroalkyl,C₃₋₆heterocyclyl, C₁₋₆alkyC₃₋₆heterocyclyl, —OH, —OR⁵, —NR³R⁴,—C(O)NR³R⁴, —CN, —S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵ or R⁷ and R⁸are taken together with the atom to which they are attached to form aring containing 0-2 heteroatoms selected from the group consisting of—O—, —NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁸ is —H and R⁷is C₁₋₆alkyl, C₁₋₆fluoroalkyl, halo, or C₃₋₆carbocyclyl. In someembodiments, R⁸ is —H and R⁷ is C₁₋₆alkyl, or C₃₋₆carbocyclyl. In someembodiments, R⁸ is —H and R⁷ is alkyl. In some embodiments, R⁸ is —H andR⁷ is methyl. In some embodiments, R⁸ is —H and R⁷ is ethyl.

In some embodiments, R⁷ and R⁸ are C₁₋₆alkyl. In some embodiments, R⁷and R⁸ are methyl. In some embodiments, R⁷ and R⁸ are halo.

In other embodiments, R⁷ and R⁸ are taken together with the atom towhich they are attached to form a 3-, 4-, 5-, or 6-membered ringcontaining 0-2 heteroatoms selected from the group consisting of —O—,—NH—, —NR⁶—, —S—, and —S(O)₂—. In some embodiments, R⁷ and R⁸ are takentogether with the atom to which they are attached to form a 3-, 4-, 5-,or 6-membered carbocycle ring. In some embodiments, R⁷ and R⁸ are takentogether with the atom to which they are attached to form a cyclopropyl.

In some embodiments, each R¹⁰ is independently hydrogen, optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl. In some embodiments, each R¹⁰ isindependently hydrogen, optionally substituted alkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, oroptionally substituted aryl. In some embodiments, each R¹⁰ isindependently optionally substituted alkyl, optionally substitutedcarbocyclyl, optionally substituted heteroalkyl, optionally substitutedaryl, or heteroaryl. In some embodiments, each R¹⁰ is independentlyalkyl or aryl. In some embodiments, each R¹⁰ is independently hydrogenor C₁₋₆ alkyl. In some embodiments, each R¹⁰ is independently hydrogen,methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl,tert-butyl, pentyl or hexyl. In some embodiments, each R¹⁰ isindependently hydrogen, methyl, ethyl, propyl, iso-propyl, butyl, ortert-butyl. In some embodiments, each R¹⁰ is independently hydrogen ormethyl. In some embodiments, R¹ is H. In other embodiments, R¹⁰ isalkyl. In other embodiments, R¹⁰ is aryl.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. Insome embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3 or 4.

In some embodiments, compounds of Formula (IV) described herein have thefollowing structure of Formula (IVa) or Formula (IVb):

wherein

-   -   ring B is an optionally substituted fused carbocyclyl,        optionally substituted fused heterocyclyl, optionally        substituted fused aryl, or optionally substituted fused        heteroaryl;    -   and n is 0, 1, 2, or 3.

In some embodiments, the substituted steroidal derivative compounddescribed in Formulas provided herein has a structure provided in Table1.

TABLE 1 Mass, Structure [M + H]⁺

534.3

507.4

556.3

472.2

456.1

480.6

486.4

405.3

506.3

444.4

506.3

494.3

536.3

570.3

458.3

498.4

493.3

506.3

459.3

500.3

444.4

534.3

551.3

448.3

429.4

431.3

427.3

415.3

431.3

445.4

443.3

453.4

455.3

440.3

415.4

419.3

459.4

431.3

423.2

444.4

459.4

430.3

463.3

472.4

456.4

472.4

451.3

435.4

464.3

448.4

461.3

460.2

444.2

444.1

 430.59

444.4

486.4

460.4

447.4

460.4

464.3

502.4

437.3

498.3

508.4

492.4

480.4

466.3

451.3

462.4

437.3

466.3

453.3

453.2

 457.66

466.3

462.4 — —

445.3

459.4

442.4

458.3

431.2

467.3

458.3

455.3

402.4

402.4

388.3 — —

479.3

493.3

451.3

563.3

500.3 — —

458.3

548.3

433.3

522.3

480.4

520.3

433.3

508.3

492.4

492.4

480.4

415.4

521.3

451.4

458.4

444.3

401.3

419.3

514.4

459.3

548.3

472.4

456.4

514.4

473.3

473.3

474.4

472.4

458.3

526.4

470.3

444.4

469.3

480.4

492.4

552.3

Preparation of the Substituted Steroidal Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. “Commercially available chemicals”are obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCompany (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.),Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan,Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics(Comwall, U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge ChemicalCo. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz &Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.), PierceChemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover, Germany),Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI America(Portland, Oreg.), Trans World Chemicals, Inc. (Rockville, Md.), andWako Chemicals USA, Inc. (Richmond, Va.).

Suitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatise that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are optionally identified through theindices of known chemicals prepared by the Chemical Abstract Service ofthe American Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (contact theAmerican Chemical Society, Washington, D.C. for more details). Chemicalsthat are known but not commercially available in catalogs are optionallyprepared by custom chemical synthesis houses, where many of the standardchemical supply houses (e.g., those listed above) provide customsynthesis services. A reference for the preparation and selection ofpharmaceutical salts of the substituted steroidal derivative compoundsdescribed herein is P. H. Stahl & C. G. Wermuth “Handbook ofPharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

The substituted steroidal derivative compounds are prepared by thegeneral synthetic route described below in Scheme 1. Furtherexemplification is found in the specific examples provided.

As shown in Scheme 1, compounds of the present invention can be preparedby reacting a ketone 1 and a commercially availableprop-1-yn-1-ylmagnesium bromide in THF to provide a compound 2.Treatment of 2 with 30% hydrogen peroxide and1,1,1,3,3,3-hexafluoropropan-2-one trihydrate in the presence of Na₂HPO₄in DCM produces an epoxide 3. Reaction of 3 with an arylmagnesiumbromide in the presence of copper (I) iodide, followed by treatment with70% acetic acid aq. solution to give compound 5. Arylmagnesium bromideis commercially available or prepared from a corresponding bromide oriodide using methods well known to those of ordinary skill in the art.

Pharmaceutical Compositions of the Substituted Steroidal DerivativeCompounds

In certain embodiments, the substituted steroidal derivative compound asdescribed herein is administered as a pure chemical. In otherembodiments, the substituted steroidal derivative compound describedherein is combined with a pharmaceutically suitable or acceptablecarrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice as described, for example, in Remington: TheScience and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co.,Easton, Pa. (2005)).

Provided herein is a pharmaceutical composition comprising at least onesubstituted steroidal derivative compound, or a stereoisomer,pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof,together with one or more pharmaceutically acceptable carriers. Thecarrier(s) (or excipient(s)) is acceptable or suitable if the carrier iscompatible with the other ingredients of the composition and notdeleterious to the recipient (i.e., the subject) of the composition.

One embodiment provides a pharmaceutical composition comprising acompound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the substituted steroidal derivative compound asdescribed by any of the Formulas provided herein is substantially pure,in that it contains less than about 5%, or less than about 1%, or lessthan about 0.1%, of other organic small molecules, such as unreactedintermediates or synthesis by-products that are created, for example, inone or more of the steps of a synthesis method.

Suitable oral dosage forms include, for example, tablets, pills,sachets, or capsules of hard or soft gelatin, methylcellulose or ofanother suitable material easily dissolved in the digestive tract. Insome embodiments, suitable nontoxic solid carriers are used whichinclude, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. (See, e.g.,Remington: The Science and Practice of Pharmacy (Gennaro, 21^(st) Ed.Mack Pub. Co., Easton, Pa. (2005)).

The dose of the composition comprising at least one substitutedsteroidal derivative compound as described herein differ, depending uponthe patient's (e.g., human) condition, that is, stage of the disease,general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Use of the Substituted Steroidal Derivative Compounds GlucocorticoidReceptor Modulators

Mifepristone is a non-selective modulator of several nuclear receptors.

Mifepristone has been referred to as a GR antagonist, a progesteronereceptor (PR) antagonist, a GR partial agonist, an androgen receptor(AR) antagonist and an AR partial agonist in the scientific literature.The activity observed at multiple hormone receptors leads to variousundesirable side effects and in some instances, the promotion of cancer.Thus, AR agonism is an undesirable feature for GR antagonists used inthe treatment of cancer (e.g., AR positive or AR dependent cancersincluding “castration resistant” prostate cancer (CRPC), breast cancer,or ovarian cancer). Antagonists of GR that have minimized binding toother hormone receptors, such as the androgen receptor (AR), are neededto effectively treat the diseases described herein with reduced sideeffects.

Some embodiments provided herein describe compounds that are modulatorsof glucocorticoid receptors (GR). In some embodiments, the compoundsalter the level and/or activity of GR. In some embodiments, thecompounds described herein are GR inhibitors. In some embodiments, theGR inhibitors are GR antagonists. In some instances, glucocorticoidreceptor antagonists bind to the receptor and prevent glucocorticoidreceptor agonists from binding and eliciting GR mediated events,including transcription. Thus, in some embodiments, the compoundsdescribed herein inhibit GR transcriptional activation activity. In someembodiments, the compounds described herein are selective GRantagonists. In some embodiments, the compounds described herein are notGR agonists. In some embodiments, the compounds described herein are notGR partial agonists. In some embodiments, the GR inhibitors lessencortisol activity in cells and make secondary therapeutic agents moreeffective.

GR antagonists are useful for treating or preventing weight gain (e.g.,Olanzapine induced weight gain), uterine fibrosis, alcoholism, alcoholabuse disorders, cocaine dependence, bipolar depression, adrenalhypercortisolism, post-traumatic stress disorder, anxiety disorders,mood disorders, hyperglycemia, and to induce abortion.

In some embodiments, the GR inhibitors described herein are alsoandrogen receptor (AR) signaling inhibitors. In certain embodiments, theAR signaling inhibitors are AR antagonists. In some instances, ARantagonists bind to AR and prevent AR agonists from binding andeliciting AR mediated events, including transcription. In otherembodiments, the GR inhibitors are not androgen receptor (AR) signalinginhibitors. In these instances, the GR inhibitors do not significantlyactivate AR levels and/or activity.

In some embodiments, the GR inhibitors described herein have minimizedbinding to the androgen receptor (AR). In some embodiments, thecompounds described herein are not AR agonists. In some embodiments, thecompounds described herein are not partial AR agonists. In someembodiments, the compounds described herein have minimized partial ARagonism compared to mifepristone.

In some embodiments, the GR inhibitors described herein are not partialAR agonists or partial GR agonists.

In some embodiments, the GR inhibitors described herein do not modulateprogesterone receptors. In some embodiments, the GR inhibitors describedherein are not progesterone receptor (PR) inhibitors. In theseinstances, the GR inhibitors do not significantly activate PR levelsand/or activity. In some embodiments, the GR inhibitors are not PRagonists. In some embodiments, the GR inhibitors are not PR partialagonists. In some embodiments, the GR inhibitors are not PR antagonists.

In some embodiments, the GR inhibitors (e.g., GR antagonists) areselective inhibitors. In some embodiments, use of the GR inhibitors in apatient does not cause or result in vaginal bleeding, cramping, nausea,vomiting, diarrhea, dizziness, back pain, weakness, tiredness, orcombinations thereof. In certain embodiments, use of the GR inhibitorsin a patient does not cause or result in vaginal bleeding. In certainembodiments, use of the GR inhibitors in a patient does not cause orresult in cramping. In some embodiments, use of the GR inhibitors in apatient does not cause or result in allergic reactions, low bloodpressure, loss of consciousness, shortness of breath, rapid heartbeat,or combinations thereof.

Methods of Treatment Cancer

One embodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a compound of any ofthe Formulas provided herein, or a pharmaceutically acceptable saltthereof. In some embodiments, a GR inhibitor described herein is used incombination with a second therapeutic agent (e.g., an anti-cancer agent)for treating cancer. In some embodiments, the combination of the GRinhibitor with the second therapeutic agent (e.g., an anti-cancer agent)provides a more effective initial therapy for treating cancer comparedto the second therapeutic agent (e.g., an anti-cancer agent)administered alone. In some embodiments, a GR inhibitor described hereinis used in combination with one or more additional therapeutic agents(e.g., anti-cancer agents) for treating cancer. In some embodiments, thecombination of the GR inhibitor with the one or more additionaltherapeutic agents (e.g., an anti-cancer agents) provides a moreeffective initial therapy for treating cancer compared to the one ormore therapeutic agents (e.g., an anti-cancer agents) administeredalone.

In some embodiments, the cancer is chemoresistant cancer, radioresistant cancer, or refractory cancer. In some embodiments, the canceris relapsed cancer, persistent cancer, or recurrent cancer. Anotherembodiment provided herein describes a method of reducing incidences ofcancer recurrence. Also provided here in some embodiments, is a methodof for treating a chemo-resistant cancer.

Prostate Cancer

Prostate cancer is the second most common cause of cancer death in menin the United States, and approximately one in every six American menwill be diagnosed with the disease during his lifetime. Treatment aimedat eradicating the tumor is unsuccessful in 30% of men.

One embodiment provides a method of treating prostate cancer in asubject in need thereof, comprising administering to the subject acompound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments, a GR inhibitor describedherein is used in combination with a second therapeutic agent (e.g., ananti-cancer agent) for treating prostate cancer. In some embodiments,the combination of the GR inhibitor with the second therapeutic agent(e.g., an anti-cancer agent) provides a more effective initial therapyfor treating prostate cancer compared to the second therapeutic agent(e.g., an anti-cancer agent) administered alone. In some embodiments, aGR inhibitor described herein is used in combination with one or moreadditional therapeutic agents (e.g., anti-cancer agents) for treatingprostate cancer. In some embodiments, the combination of the GRinhibitor with the one or more additional therapeutic agents (e.g., ananti-cancer agents) provides a more effective initial therapy fortreating prostate cancer compared to the one or more therapeutic agents(e.g., an anti-cancer agents) administered alone.

In some embodiments, the prostate cancer is chemoresistant cancer, radioresistant cancer, antiandrogen resistant, or refractory cancer. In someembodiments, the prostate cancer is relapsed cancer, persistent cancer,or recurrent cancer.

In some embodiments, the prostate cancer is acinar adenocarcinoma,atrophic carcinoma, foamy carcinoma, colloid carcinoma, or signet ringcarcinoma. In some embodiments, the prostate cancer is ductaladenomcarcinoma, transitional cell cancer, urothelial cancer, squamouscell cancer, carcinoid cancer, small cell cancer, sarcoma cancer, orsarcomatoid cancer. In some embodiments, the prostate cancer ismetastatic castration-resistant prostate cancer, doubly-resistantprostate cancer, castration-resistant prostate cancer, hormone-resistantprostate cancer, androgen-independent, or androgen-refractory cancer.

In some instances, antiandrogens are useful for the treatment ofprostate cancer during its early stages. In some instances, prostatecancer cells depend on androgen receptor (AR) for their proliferationand survival. Some prostate cancer patients are physically castrated orchemically castrated by treatment with agents that block production oftestosterone (e.g. GnRH agonists), alone or in combination withantiandrogens, which antagonize effects of any residual testosterone.

In some instances, prostate cancer advances to a hormone-refractorystate in which the disease progresses despite continued androgenablation or antiandrogen therapy. The hormone-refractory state to whichmost patients eventually progresses in the presence of continuedandrogen ablation or anti-androgen therapy is known as “castrationresistant” prostate cancer (CRPC). CRPC is associated with anoverexpression of AR. AR is expressed in most prostate cancer cells andoverexpression of AR is necessary and sufficient forandrogen-independent growth of prostate cancer cells. Failure inhormonal therapy, resulting from development of androgen-independentgrowth, is an obstacle for successful management of advanced prostatecancer.

While a small minority of CRPC does bypass the requirement for ARsignaling, the vast majority of CRPC, though frequently termed “androgenindependent prostate cancer” or “hormone refractory prostate cancer,”retains its lineage dependence on AR signaling.

Recently approved therapies that target androgen receptor (AR) signalingsuch as abiraterone and enzalutamide have been utilized for treatingCRPC. Despite these successes, sustained response with these agents islimited by acquired resistance which typically develops within 6-12months. Doubly resistant prostate cancer is characterized in that tumorcells have become castration resistant and overexpress AR, a hallmark ofCRPC. However, cells remain resistant when treated with secondgeneration antiandrogens. Doubly resistant prostate cancer cells arecharacterized by a lack of effectiveness of second generationantiandrogens in inhibiting tumor growth.

As discussed above, resistant prostate cancer (e.g., doubly resistantand castration resistant prostate cancers) occurs when cancer cellsoverexpress androgen receptors (AR). AR target gene expression isinhibited when the cells are treated with a second generationantiandrogen. In some instances, increased signaling through theglucocorticoid receptor (GR) compensates for inhibition of androgenreceptor signaling in resistant prostate cancer. Double resistantprostate cancer develops when expression of a subset of those AR targetgenes is restored. In some instances, GR activation is responsible forthis target gene activation. In some embodiments, GR transcription isactivated in patients susceptible to or suffering from resistantprostate cancer (e.g., doubly resistant and castration resistantprostate cancers). In some instances, GR upregulation in cancer cellsconfers resistance to antiandrogens.

Some embodiments provided herein describe the use of the GR inhibitorsfor treating prostate cancer in a subject in need thereof, includingdoubly resistant prostate cancer and castration resistant prostatecancer. In some embodiments, the subject in need has elevated tumor GRexpression. In some embodiments, the GR inhibitor is also an ARsignaling inhibitor or antiandrogen.

In some embodiments, the GR inhibitor is used in combination with asecond therapeutic agent. In some embodiments, the GR inhibitor is usedin combination with one or more additional therapeutic agents. In someembodiments, the second or additional agent is an anti-cancer agent. Incertain embodiments, the anti-cancer agent is useful for AR positive orAR negative prostate cancer.

In some embodiments, the second or additional agent is an AR signalinginhibitor or antiandrogen. In certain embodiments, the AR signalinginhibitor is an AR antagonist. In some embodiments, the second oradditional therapeutic agent is selected from finasteride, dutasteride,alfatradiol, cyproterone acetate, spironolactone, danazol, gestrinone,ketoconazole, abiraterone acetate, enzalutamide, ARN-509, danazol,gestrinone, danazol, simvastatin, aminoglutethimide, atorvastatin,simvastatin, progesterone, cyproterone acetate, medroxyprogesteroneacetate, megestrol acetate, chlormadinone acetate, spironolactone,drospirenone, estradiol, ethinyl estradiol, diethylstilbestrol,conjugated equine estrogens, buserelin, deslorelin, gonadorelin,goserelin, histrelin, leuprorelin, nafarelin, triptorelin, abarelix,cetrorelix, degarelix, ganirelix, or any combinations or any saltsthereof. In some embodiments, the second or additional therapeutic agentis selected from flutamide, nilutamide, bicalutamide, enzalutamide,apalutamide, cyproterone acetate, megestrol acetate, chlormadinoneacetate, spironolactone, canrenone, drospirenone, ketoconazole,topilutamide, cimetidine, or any combinations or any salts thereof. Insome embodiments, the AR signaling inhibitor is 3,3′-diindolylmethane(DIM), abiraterone acetate, ARN-509, bexlosteride, bicalutamide,dutasteride, epristeride, enzalutamide, finasteride, flutamide,izonsteride, ketoconazole, N-butylbenzene-sulfonamide, nilutamide,megestrol, steroidal antiandrogens, turosteride, or any combinationsthereof. In some embodiments, the AR signaling inhibitor is flutamide,nilutamide, bicalutamide, or megestrol. In some embodiments, the ARsignaling inhibitor is ARN-509. In other embodiments, the AR signalinginhibitor is enzalutamide.

In some embodiments, the anti-cancer agent is mitoxantrone,estramustine, etoposide, vinblastine, carboplatin, vinorelbine,paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel,or doxorubicin. In some embodiments, the anti-cancer agent ispaclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel,or doxorubicin. In certain embodiments, the anti-cancer agent isdocetaxel.

Breast Cancer

Breast cancer is the second leading cause of cancer among women in theUnited States. Triple-negative breast cancers are among the mostaggressive and difficult to treat of all the breast cancer types.Triple-negative breast cancer is a form of the disease in which thethree receptors that fuel most breast cancer growth—estrogen,progesterone and the HER-2—are not present. Because the tumor cells lackthese receptors, treatments that target estrogen, progesterone and HER-2are ineffective. Approximately 40,000 women are diagnosed withtriple-negative breast cancer each year. It is estimated that more thanhalf of these women's tumor cells express significant amounts of GR.

In some instances, GR expression is associated with a poor prognosis inestrogen receptor (ER)-negative early stage breast cancer. In someinstances, GR activation in triple-negative breast cancer cellsinitiates an anti-apoptotic gene expression profile that is associatedwith inhibiting chemotherapy-induced tumor cell death. GR activity inthese cancer cells correlate with chemotherapy resistance and increasedrecurrence of cancer.

Provided herein in some embodiments are methods of treating breastcancer, the method comprising administering to a subject in need thereofa compound of any of the Formulas provided herein, or a pharmaceuticallyacceptable salt thereof. In some embodiments, a GR inhibitor describedherein is used in combination with a second therapeutic agent (e.g., achemotherapeutic agent) for treating breast cancer. In some embodiments,the combination of the GR inhibitor with the second therapeutic agent(e.g., a chemotherapeutic agent) provides a more effective initialtherapy for treating breast cancer compared to the second therapeuticagent (e.g., a chemotherapeutic agent) administered alone. In someembodiments, a GR inhibitor described herein is used in combination withone or more additional therapeutic agents (e.g., anti-cancer agents) fortreating breast cancer. In some embodiments, the combination of the GRinhibitor with the one or more additional therapeutic agents (e.g., ananti-cancer agents) provides a more effective initial therapy fortreating breast cancer compared to the one or more therapeutic agents(e.g., an anti-cancer agents) administered alone.

In some embodiments, the breast cancer is chemoresistant cancer, radioresistant cancer, or refractory cancer. In some embodiments, the breastcancer is relapsed cancer, persistent cancer, or recurrent cancer.Breast cancers may include, but are not limited to, ductal carcinoma,invasive ductal carcinoma, tubular carcinoma of the breast, medullarycarcinoma of the breast, mecinous carcinoma of the breast, papillarycarcinoma of the breast, cribriform carcinoma of the breast, invasivelobular carcinoma, inflammatory breast cancer, lobular carcinoma insitu, male breast cancer, Paget disease of the nipple, phyllodes tumorof the breast, recurrent and metastatic breast cancer, triple-negativebreast cancer, or combinations thereof.

In some embodiments, the breast cancer is recurrent and metastaticbreast cancer, triple-negative breast cancer, or combinations thereof.In some embodiments, the breast cancer is chemoresistant triple-negativebreast cancer or estrogen receptor (ER) negative breast cancer. In someembodiments, the breast cancer is chemoresistant triple-negative breastcancer. In some embodiments, the breast cancer is estrogen receptor (ER)negative breast cancer. In some embodiments, the breast cancer is GR+triple-negative breast cancer. In some embodiments, the breast cancer isGR+ estrogen receptor (ER) negative breast cancer.

Some embodiments provided herein describe the use of GR inhibitors fortreating breast cancer in a patient, including triple negative breastcancer or ER negative breast cancer. In some embodiments, GR inhibitorsinhibit the anti-apoptotic signaling pathways of GR and increase thecytotoxic efficiency of secondary chemotherapeutic agents. In someembodiments, the GR inhibitors described herein enhance the efficacy ofchemotherapy in breast cancer patients, such as triple negative breastcancer patients. In some embodiments, the breast cancer patient haselevated tumor GR expression.

In some embodiments, a GR inhibitor described herein is used incombination with a second therapeutic agent, such as chemotherapy orimmunotherapy. In some embodiments, a GR inhibitor described herein isused in combination with one or more additional therapeutic agents. Insome embodiments, the second or additional chemotherapeutic agent iscisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine,paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin,melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide,irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin,camptothecin, pemetrexed, topotecan, vinorelbine, daunorubicin,fluorouracil, mitomycin, thiotepa, vincristine, everolimus, veliparib,glembatumumab vedotin, pertuzumab, trastuzumab, or any combinations orany salts thereof. In some embodiments, the second or additionaltherapeutic agent is an anti-PD-L1 agent. In certain embodiments, theanti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, thesecond or additional therapeutic agent is an anti-PD1 agent. In certainembodiments, the anti-PD1 agent is nivolumab or permbrolizumab.

Some embodiments provided herein describe methods of treating estrogenpositive breast cancer. In some instances, estrogen positive breastcancer patients become resistant to estrogen receptor modulators. Insome embodiments, the GR inhibitors described herein enhance theefficacy of estrogen receptor modulators in estrogen positive breastcancer patients. In some embodiments, the breast cancer patient haselevated tumor GR expression. In some embodiments, a GR inhibitordescribed herein is used in combination with an estrogen receptormodulator. In some embodiments, the estrogen receptor modulator istamoxifen, raloxifene, toremifene, tibolone, fulvestrant, lasofoxifene,clomifene, ormeloxifene, or ospemifene. In some embodiments, theestrogen receptor modulator is tamoxifen, raloxifene, toremifene,tibolone, or fulvestrant. In some embodiments, the estrogen receptormodulator is tamoxifen, raloxifene, or toremifene. In certainembodiments, the estrogen receptor modulator is tamoxifen.

Ovarian Cancer

Ovarian cancer is the leading cause of death from gynecologicmalignancies. Some ovarian cancers (e.g., high grade serous ovariancancer) are initially sensitive to platinum-based therapy, but relapserates remain high.

One embodiment provides a method of treating ovarian cancer in a patientin need thereof, comprising administering to the patient a compound ofany of the Formulas provided herein, or a pharmaceutically acceptablesalt thereof. In some embodiments, the patient has elevated tumor GRexpression. In some embodiments, a GR inhibitor described herein is usedin combination with a second therapeutic agent (e.g., a chemotherapeuticagent) for treating ovarian cancer. In some embodiments, the combinationof the GR inhibitor with the second therapeutic agent (e.g., achemotherapeutic agent) provides a more effective initial therapy fortreating ovarian cancer compared to the second therapeutic agent (e.g.,a chemotherapeutic agent) administered alone. In some embodiments, a GRinhibitor described herein is used in combination with one or moreadditional therapeutic agents (e.g., anti-cancer agents) for treatingovarian cancer. In some embodiments, the combination of the GR inhibitorwith the one or more additional therapeutic agents (e.g., an anti-canceragents) provides a more effective initial therapy for treating ovariancancer compared to the one or more therapeutic agents (e.g., ananti-cancer agents) administered alone.

In some instances, GR activation increases resistance to chemotherapy inovarian cancer (e.g., high-grade serous ovarian cancer). In someinstances, GR activation significantly inhibits chemotherapy inducedapoptosis in ovarian cancer cells. Provided herein in some embodimentsare methods of treating ovarian cancer in a subject, the methodcomprising treating the subject with a GR inhibitor (e.g., GRantagonist) to improve sensitivity to chemotherapy. In some embodiments,the ovarian cancer has become resistant to chemotherapy. In someembodiments, the ovarian cancer cells are resistant to cisplatin,paclitaxel, carboplatin, gemcitabine, alone or in combination. In someembodiments, the GR inhibitor or antagonist reverses the cell survivaleffect.

Ovarian cancers may include, but are not limited to, epithelial ovariancancers, such as serous epithelial ovarian cancer, endometrioidepithelial ovarian cancer, clear cell epithelial ovarian cancer,mucinous epithelial ovarian cancer, undifferentiated or unclassifiableepithelial ovarian cancer, refractory ovarian cancer, sex cord-stromaltumors, Sertoli and Sertoli-Leydig cell tumors, germ cell tumors, suchas dysgerminoma and nondysgerminomatous tumors, Brenner tumors, primaryperitoneal carcinoma, fallopian tube cancer, or combinations thereof.

In some embodiments, the GR inhibitor is used in combination with atleast a second therapeutic agent, such as chemotherapy or immunotherapy.In some embodiments, the GR inhibitor is used in combination with one ormore additional therapeutic agents. In some embodiments, the second oradditional chemotherapeutic agent is cisplatin, carboplatin,cyclophosphamide, capecitabine, gemcitabine, paclitaxel, nab-paclitaxel,altretamine, docetaxel, epirubicin, melphalan, methotrexate,mitoxantrone, ixabepilone, ifosfamide, irinotecan, eribulin, etoposide,doxorubicin, liposomal doxorubicin, camptothecin, pemetrexed, topotecan,vinorelbine, daunorubicin, fluorouracil, mitomycin, thiotepa,vincristine, everolimus, veliparib, glembatumumab vedotin, pertuzumab,trastuzumab, or any combinations or any salts thereof. In someembodiments, the second or additional chemotherapeutic agent isgemcitabine. In some embodiments, the second or additionalchemotherapeutic agent is carboplatin. In some embodiments, the secondor additional chemotherapeutic agent is cisplatin. In some embodiments,the second or additional agent is paclitaxel. In some embodiments, theGR inhibitor is used in combination with gemcitabine and carboplatin. Insome embodiments, the GR inhibitor is used in combination withcarboplatin and cisplatin. In some embodiments, the second or additionaltherapeutic agent is an anti-PD-L1 agent. In certain embodiments, theanti-PD-L1 agent is MPDL3280A or avelumab. In some embodiments, thesecond or additional therapeutic agent is an anti-PD1 agent. In certainembodiments, the anti-PD1 agent is nivolumab or permbrolizumab.

Non-Small Cell Lung Cancer

One embodiment provides a method of treating non-small cell lung cancer(NSCLC) in a patient in need thereof, comprising administering to thepatient a compound of any of the Formulas provided herein, or apharmaceutically acceptable salt thereof. In some embodiments, thepatient has elevated tumor GR expression. In some embodiments, a GRinhibitor described herein is used in combination with a secondtherapeutic agent (e.g., a chemotherapeutic agent) for treating NSCLC.In some embodiments, the combination of the GR inhibitor with the secondtherapeutic agent (e.g., a chemotherapeutic agent) provides a moreeffective initial therapy for treating NSCLC compared to the secondtherapeutic agent (e.g., a chemotherapeutic agent) administered alone.In some embodiments, a GR inhibitor described herein is used incombination with one or more additional therapeutic agents (e.g.,anti-cancer agents) for treating NSCLC. In some embodiments, thecombination of the GR inhibitor with the one or more additionaltherapeutic agents (e.g., an anti-cancer agents) provides a moreeffective initial therapy for treating NSCLC compared to the one or moretherapeutic agents (e.g., an anti-cancer agents) administered alone.

In some embodiments, the GR inhibitor is used in combination with atleast a second therapeutic agent, such as a chemotherapeutic agent orimmunotherapy. In some embodiments, the GR inhibitor is used incombination with one or more additional therapeutic agents. In someembodiments, the second or additional chemotherapeutic agent iscisplatin, carboplatin, cyclophosphamide, capecitabine, gemcitabine,paclitaxel, nab-paclitaxel, altretamine, docetaxel, epirubicin,melphalan, methotrexate, mitoxantrone, ixabepilone, ifosfamide,irinotecan, eribulin, etoposide, doxorubicin, liposomal doxorubicin,camptothecin, pemetrexed, topotecan, vinorelbine, vinblastine,daunorubicin, fluorouracil, mitomycin, thiotepa, vincristine,everolimus, veliparib, glembatumumab vedotin, pertuzumab, trastuzumab,or any combinations or any salts thereof. In some embodiments, thesecond or additional chemotherapeutic agent is gemcitabine. In someembodiments, the second or additional chemotherapeutic agent iscarboplatin. In some embodiments, the second or additionalchemotherapeutic agent is cisplatin. In some embodiments, the second oradditional agent is paclitaxel. In some embodiments, the GR inhibitor isused in combination with gemcitabine and carboplatin. In someembodiments, the GR inhibitor is used in combination with carboplatinand cisplatin. In some embodiments, the second or additional therapeuticagent is an anti-PD-L1 agent. In certain embodiments, the anti-PD-L1agent is MPDL3280A or avelumab. In some embodiments, the second oradditional therapeutic agent is an anti-PD1 agent. In certainembodiments, the anti-PD1 agent is nivolumab or permbrolizumab.

Hypercortisolism/Cushing's Disease

One embodiment provides a method of treating hypercortisolism orCushing's disease in a patient in need thereof, comprising administeringto the patient a compound of any of the Formulas provided herein, or apharmaceutically acceptable salt thereof.

Types of Cushing's disease include, but are not limited to, recurrentCushing's disease, refractory Cushing's disease, persistent Cushing'sdisease, endogenous Cushing's disease, spontaneous hypercortisolism,Adrenocorticotropic hormone dependent, Adrenocorticotropic hormoneindependent, or combinations thereof.

Causes of hypercortisolism may include, but are not limited to,prolonged exposure to cortisol, a tumor that produces excessivecortisol, a tumor that results in the excess production of cortisol, orcombinations thereof.

Other embodiments and uses will be apparent to one skilled in the art inlight of the present disclosures. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted.

The substituted steroidal derivative compounds are prepared by thegeneral synthetic route described in Scheme 1.

Example 1: Synthesis of(8S,11R,13S,14S,17S)-11-(3,5-Difluoro-4-methylphenyl)-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8S,13S,14S,17S)-13-Methyl-17-(prop-1-yn-1-yl)-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol

To a stirred solution of(8S,13S,14S)-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one(3.4 g, 10.9 mmol) in THF (45 mL) at 0° C. was addedbromo(prop-1-ynyl)magnesium (0.5 M in THF, 65.4 mL, 32.7 mmol) slowly.The reaction was allowed to warm up to rt and stirred for 60 min. Thereaction mixture was quenched (sat. NH₄Cl), extracted (EtOAc), andwashed (brine). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography to provide 3.0 g of the title compound as a whitesolid.

Step B.(5′R,8′S,10′R,13′S,14′S,17′S)-13′-Methyl-17′-(prop-1-yn-1-yl)-1′,2′,7′,8′,12′,13′,14′,15′,16′,17′-decahydro-4′H,6′H-spiro[[1,3]dioxolane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17′-ol

To a stirred solution of(13S,16R,17S)-13-methyl-17-prop-1-ynyl-spiro[1,2,4,6,7,8,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,2′-1,3-dioxolane]-17-ol(Step A) (2.88 g, 8.14 mmol) in DCM (60 mL) at 0° C. was added Na₂HPO₄(2.89 g, 20.35 mmol), followed by hexafluoroacetone trihydrate (1.12 mL,8.14 mmol) and H₂O₂ (30% aq, 2.0 mL, 24.4 mmol). The mixture was stirredat 0° C. for 10 min and then at rt for 2 h. The resulting mixture wascooled in ice bath and 10% Na₂S₂O₃ aq. solution (8 ml) was added slowly.After being stirred at rt for 30 min, the mixture was quenched (sat.NH₄Cl), extracted (2× EtOAc), and washed (brine). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure. Theresidue was purified by flash column chromatography to provide 1.8 g ofthe title compound as a white solid.

Step C.(5R,8S,11R,13S,14S,17S)-11-(3,5-Difluoro-4-methylphenyl)-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane]-5,17(4H)-diol

A small piece of iodine was added to magnesium pieces (757.88 mg, 31.18mmol) under argon and the mixture was heated with heat-gun to activatemagnesium metal. A solution of 5-bromo-1,3-difluoro-2-methylbenzene(5.28 g, 25.5 mmol) in THF (25 mL) was added to the mixture dropwise.The mixture was stirred at rt for 30 min and then at 55° C. for 1 h. Toa solution of copper(I) iodide (539.8 mg, 2.8 mmol) and(5′R,8′S,10′R,13′5,14′S,17′S)-13′-methyl-17′-(prop-1-yn-1-yl)-1′,2′,7′,8′,12′,13′,14′,15′,16′,17′-decahydro-4′H,6′H-spiro[[1,3]dioxolane-2,3′-[5,10]epoxycyclopenta[a]phenanthren]-17′-ol(Step B) (2.1 g, 5.67 mmol) in THF (60 mL) was added the Grignardreagent (26 mL) prepared above dropwise at 0° C. After being stirred at0° C. for 30 min, the reaction mixture was quenched (sat. NH₄Cl),extracted (EtOAc), and washed (brine). The combined organic layers weredried (Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by flash column chromatography provided the title compound as acolorless foam.

Step D.(8S,11R,13S,14S,17S)-11-(3,5-Difluoro-4-methylphenyl)-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

A solution of(5R,8S,11R,13S,14S,17S)-11-(3,5-Difluoro-4-methylphenyl)-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane]-5,17(4H)-diol(Step C) (2.0 g, 4.0 mmol) in 70% acetic acid aq. solution (8.0 mL) wasstirred at 55° C. for 1.5 h. The reaction mixture was cooled to rt,quenched (sat. NaHCO₃), extracted (EtOAc), and washed (brine). Thecombined organic layers were dried (MgSO4), and concentrated underreduced pressure. Purification of the residue by flash columnchromatography provided 1.3 g of the title compound as a white solid. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 6.65-6.73 (2H, m),5.82 (1H, s), 4.37(1H, brd, J=7.45 Hz),2.69-2.81 (1H, m),2.57-2.65 (2H, m), 2.22-2.52 (6H,m), 2.16 (3H, s), 2.08-1.94 (3H, m), 1.92 (3H, s), 1.66-1.84 (2H, m),1.32-1.53 (2H, m), 0.55 (3H, s). m/z (ESI, +ve ion) 437.3 (M+H)⁺.

Example 2: Synthesis of(8S,11R,13S,14S,16R,17S)-11-(4-(Dimethylamino)phenyl)-16-ethyl-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-oneor(8S,11R,13S,14S,16S,17S)-11-(4-(dimethylamino)phenyl)-16-ethyl-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8S,13S,14S,16R)-16-Ethyl-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-oneor(8S,13S,14S,16S)-16-ethyl-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one

A solution of(8S,13S,14S)-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one(1.00 g, 3.18 mmol) and 0.8 mL of DMPU in THF (3 mL) was added dropwiseto a solution [bis(trimethylsilyl)amino]lithium (6.36 mL, 6.36 mmol) inTHF (10 mL) at −45° C. After being stirred at −40° C. for 30 min,iodoethane (1.28 mL, 15.9 mmol) was added. The reaction was allowed towarm up to rt and stirred for another 1 h. The reaction was quenchedwith sat. NH₄Cl, extracted with EtOAc. The organics were washed withwater, brine solution, separated, and dried (Na₂SO₄) beforeconcentrating to dryness. The crude was purified by flash columnchromatography to give the title compound as a white solid.

Step B.(8S,11R,13S,14S,16R,17S)-11-(4-(Dimethylamino)phenyl)-16-ethyl-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-oneor(8S,11R,13S,14S,16S,17S)-11-(4-(dimethylamino)phenyl)-16-ethyl-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

The title compound was prepared from(8S,13S,14S,16R)-16-ethyl-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-oneor(8S,13S,14S,16S)-16-ethyl-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one(Step A) by procedures similar to those described in Example 1, StepsA-D. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.01 (2H, d, J=8.4 Hz), 6.60 (2H, d,J=8.4 Hz), 5.75 (1H, s), 4.36 (1H, d, J=6.2 Hz), 2.90 (6H, s), 2.80-1.91(8H, m), 1.90 (3H, s), 1.75-1.20 (9H, m), 0.91 (3H, t, J=5.6 Hz), 0.56(3H, s). m/z (ESI, +ve ion) 458.3 (M+H)⁺.

Example 3: Synthesis of(8S,11R,13S,14S,17S)-11-(3,5-dichloro-4-(dimethylamino)phenyl)-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

Trichloroisocyanuric acid (63.4 mg, 0.246 mmol) was added to a solutionof mifepristone [TCI M1732] (0.157 g, 0.366 mmol) in DCM (1.5 ml). Theslurry was allowed to stir at rt for 15 h. Water and more DCM were addedand the mixture was washed with sat. NaHCO₃ solution. The organic layerwas dried over magnesium sulfate, filtered and concentrated undervacuum. The residue was fractionated by silica gel chromatography.Fractions containing the desired compound were combined and repurifiedby flash chromatography to afford 33.5 mg (18%) of the title compound.¹H NMR (400 MHz, CDCl3) δ ppm 7.05 (2H, s), 5.81 (1H, s), 4.32 (1H, d,J=7.2 Hz) 2.87 (6H, s), 2.60 (1H, br s) 1.7-2.9 (17H, various m), 1.58(2H, br s), 0.55 (3H, s). m/z (ESI, +ve ion) 498.3, 500.3 [Cl2 isotopepattern] (M+H)⁺

Example 4.(8S,11R,13S,14S,17S)-11-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl-d3)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

Step A.(8S,13S,14S,17R)-17-Ethynyl-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol

To a stirred solution of(8S,13S,14S)-13-methyl-1,4,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17(2H)-one(2 g, 6.4 mmol) in THF (12 mL) at 0° C. was added ethynylmagnesiumbromide (0.5 M in THF, 44.5 mL, 22.3 mmol) slowly. The reaction wasallowed to warm up to rt and stirred for 60 min. The reaction mixturewas quenched (sat. NH₄Cl), extracted (EtOAc), and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified by flash columnchromatography to provide 1.1 g of the title compound as a white solid.

Step B.(8S,13S,14S,17S)-13-Methyl-17-(prop-1-yn-1-yl-d3)-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol

N-Butyllithium (1.84 mL, 2.94 mmol) was added to a solution of(8S,13S,14S,17R)-17-ethynyl-13-methyl-spiro[1,2,4,6,7,8,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,2′-1,3-dioxolane]-17-ol(Step A) (500 mg, 1.47 mmol) in THF (2 mL) at 0° C. After being stirredat 0° C. for 10 min, trideuterio(iodo)methane (0.1 mL, 1.62 mmol) wasadded slowly. The reaction was stirred at rt overnight, then quenchedwith sat. NH₄Cl, and extracted with EtOAc. The organics were washed withwater and brine solution, separated and dried (MgSO₄) beforeconcentration to dryness. The crude material was purified by flashcolumn chromatography to give the title compound as a white solid.

Step C.(8S,11R,13S,14S,17S)-11-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-17-hydroxy-13-methyl-17-(prop-1-yn-1-yl-d3)-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one

The title compound was prepared from(8S,13S,14S,17S)-13-methyl-17-(prop-1-yn-1-yl-d3)-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol(Step B) by procedures similar to those described in Example 1, Steps B,C and D, substituting (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesiumbromide for (3,5-difluoro-4-methylphenyl)magnesium bromide in Step C. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 6.74-6.83 (1H, m),6.65-6.67 (2H,m),5.77 (1H, s), 4.32-4.39 (1H, m),4.25 (4H, s),2.72-2.83 (1H,m),2.54-2.62 (2H, m),2.30-2.51 (4H, m),2.20-2.28 (2H, m), 1.97-2.08 (2H,m), 1.90-1.97 (1H, m), 1.57-1.83 (2H, m), 1.29-1.56 (2H, m), 0.56 (3H,s). m/z (ESI, +ve ion) 448.3 (M+H)⁺.

II. Biological Evaluation Example 5: In Vitro GR Luciferase ReporterAssay

Cell Line: CHO-K1-GR-MMTV-Luc reporter cellsCulture Media: DMEM (with phenol red)+10% FBSAssay Media: DMEM (without phenol red)+10% CSS

Culture CHO-K1-GR-MMTV-Luc reporter cells in 15 cm plates in CultureMedia at conditions less than 90% confluence.

Prepare 200×DMSO 1:5 serial dilutions of control and test compounds in96-well non-sterile V bottom plate in DMSO, 8 serial dilutions for eachcompound.

Prepare 5× Assay Media diluted compound serial dilutions in 96-wellnon-sterile V bottom plate: Add 97.5 uL/well of Assay Media into 96-wellthen add 2.5 ul of 200× concentration of compounds and mix well.

Seed cells for Antagonist Assay: 1.5×10⁶ CHO-K1-GR-MMTV-Luc reportercells were seeded in a Corning 3707 flat clear bottom 384-well white TCplate in 20 ul of Assay Media containing 12.5 nM Dexamethasone (finalconcentration=10 nM).

Add compounds: 5 ul of assay media diluted compounds were added toappropriate wells and followed a quick spin (1000 rpm, 10 sec) to bringmedia and cells to the bottom of plate. The plates were covered withSealMate film to avoid evaporation and placed in 37° C. incubator forapproximately 18-24 hours.

Read plates: Equilibrate appropriate amount of Promega OneGlo luciferasereagent to room temperature. Remove the plates from incubator and add 25uL of OneGlo reagent/well by multiple channel pipette and read theplates with Tecan F500 luminometer within 3 minutes.

The ability of the compounds disclosed herein to inhibit GR activity wasquantified and the respective IC₅₀ value was determined. Table 2provides the cellular IC₅₀ values of various substituted steroidalcompounds disclosed herein.

TABLE 2 GR IC₅₀ Structure (nM)

A

A

B

B

A

A

A

A

A

B

B

A

A

A

A

A

A

A

A

A

A

B

B

B

B

B

B

B

A

A

A

A

A

A

A

A

A

A

A

A

A

B

B

A

A

A

A

A

A

A

A

A

A

A

A

B

B

B

A

A Note: Cellular assay IC₅₀ data are designated within the followingranges: A: ≤ 100 nM B: > 100 nM

Example 6: In Vitro AR Agonism Assay

The AR agonism assay was done in the LNAR reporter cell line which hasoverexpressed AR and 4XARE-Luc genes. This cell line is sensitive toeven minor partial AR agonism activity in hormone-deprived media (CSS).The assays were done in RPMI (without phenol red)+10% CSS using 6000LNAR cells/well in 384-well plates and compounds were incubated withcells in 370 C incubator for 18-24 hrs. OneGlo reagent (25 uL/well) wasadded and plates were read with luminometer within 3 minutes.

Mifepristone shows strong partial AR agonism in concentrations as low as10 nM, and is known to significantly promote CRPC growth both in vivoand in vitro. To gauge the AR partial agonism activity, Mifepristone isincluded as a standard in the assay. AR agonism assay results arequantified by determining the ratio of the maximum response ofindividual compounds to the maximum response of Mifepristone(arbitrarily set to 1). Values of Table 3 are reported as RelativeMaximum Response to Mifepristone. This general trend of AR agonism wasshown for the class of compounds described herein.

TABLE 3 Relative Maximum Response to Structure Mifepristone

A

A

A

A

A

A

B

A

A

A

A

A

A

A

A

B Note: AR agonism response assay data relative maximum response toMifepristone is designated within the following ranges: A: ≤ 0.4 B: >0.4

1. A compound having the structure of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof:

wherein R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkyNR³S(O)₂R⁶,-alkyNR³S(O)₂NR³R⁴, —NR³S(O)R⁶, —NR³aralkyl, —Oaralkyl, —C(O)NR³R⁴,—OC(O)OR⁵, —C(O)OR⁵, —OC(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁶, —S(O)R⁶, or—SR⁶; R³ and R⁴ are each independently —H, optionally substituted alkyl,haloalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heteroalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,—S(O)₂R⁶, —C(O)N(R¹⁰)₂, —C(O)R⁵, or —C(O)OR⁵; or R³ and R⁴ attached tothe same N atom are taken together with the N atom to which they areattached to form a substituted or unsubstituted heterocycle; R⁵ isoptionally substituted alkyl, haloalkyl, optionally substitutedcarbocyclyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl; R⁶ is optionallysubstituted alkyl, haloalkyl, optionally substituted carbocyclyl,optionally substituted heteroalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl; R⁷ and R⁸ are each independently —H,optionally substituted alkyl, haloalkyl, halo, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heteroalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —OH, —OR⁵, —NR³R⁴, —C(O)NR³R⁴, —CN,—S(O)₂R⁶, —C(O)₂H, —C(O)R⁵, or —C(O)OR⁵; or R⁷ and R⁸ are taken togetherwith the atom to which they are attached to form a substituted orunsubstituted ring containing 0-2 heteroatoms selected from the groupconsisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and each R¹⁰ isindependently H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl.
 2. The compound ofclaim 1 or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R¹ is —NR³S(O)₂R⁶, —NR³S(O)₂NR³R⁴, -alkyNR³S(O)₂R⁶,-alkyNR³S(O)₂NR³R⁴, —NR³aralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, or —S(O)₂R⁶;R³ and R⁴ are each independently —H, optionally substituted alkyl,fluoroalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted aryl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶; or R³ and R⁴ attachedto the same N atom are taken together with the N atom to which they areattached to form a substituted or unsubstituted 3-, 4-, 5-, or6-membered heterocycle; R⁵ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl; R⁶ is optionally substituted alkyl, fluoroalkyl,optionally substituted carbocyclyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl; R⁷ and R⁸ are each independently —H,optionally substituted alkyl, fluoroalkyl, halo, —OR⁵, —NR³R⁴,—C(O)NR³R⁴, —CN, optionally substituted carbocyclyl, or optionallysubstituted carbocyclylalkyl; or R⁷ and R⁸ are taken together with theatom to which they are attached to form a substituted or unsubstituted3-, 4-, 5-, or 6-membered ring containing 0-2 heteroatoms selected fromthe group consisting of —O—, —NH—, —NR⁶—, —S—, and —S(O)₂—; and each R¹⁰is independently H, optionally substituted alkyl, haloalkyl, optionallysubstituted carbocyclyl, optionally substituted heteroalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl.
 3. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein R¹ is —NR³S(O)₂R⁶, —NR³aralkyl, —C(O)NR³R⁴,—S(O)₂NR³R⁴, or —S(O)₂R⁶.
 4. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR¹ is —NR³S(O)₂R⁶ or —S(O)₂NR³R⁴.
 5. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR³ and R⁴ are each independently —H, optionally substituted alkyl,fluoroalkyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, —C(O)N(R¹⁰)₂, or —S(O)₂R⁶.
 6. Thecompound of claim 1, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R³ and R⁴ are each independently —H, alkyl, or—S(O)₂R⁶.
 7. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein R³ and R⁴ attached to thesame N atom are taken together with the N atom to which they areattached to form a substituted or unsubstituted 4-, 5-, or 6-memberedring heterocycle containing 0-3 heteroatoms selected from —O—, —NH—,—NR⁵—, —S—, and —S(O)₂—; and R⁵ is alkyl.
 8. The compound of claim 1, ora pharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR⁶ is alkyl, carbocyclyl, optionally substituted aryl, optionallysubstituted aralkyl, or optionally substituted heterocyclyl.
 9. Thecompound of claim 8, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R⁶ is C₁₋₆ alkyl, C₃₋₆ carbocyclyl, optionallysubstituted phenyl, optionally substituted benzyl, or optionallysubstituted heterocyclyl.
 10. The compound of claim 1, or apharmaceutically acceptable salt, solvate, or prodrug thereof, whereinR⁷ and R⁸ are each independently —H, alkyl, or carbocyclyl.
 11. Thecompound of claim 10, or a pharmaceutically acceptable salt, solvate, orprodrug thereof, wherein R⁷ and R⁸ are —H. 12.-41. (canceled)
 42. Apharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt, solvate, or prodrug thereof, and atleast one pharmaceutically acceptable excipient.
 43. (canceled)
 44. Amethod for treating cancer in a subject, the method comprisingadministering a therapeutically effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, or prodrugthereof, to the subject in need thereof.
 45. (canceled)
 46. A method ofreducing incidences of cancer recurrence in a subject in cancerremission, the method comprising administering to the subject atherapeutically effective amount of the compound of claim 1, or apharmaceutically acceptable salt, solvate, or prodrug thereof. 47.(canceled)
 48. A method for treating a chemo-resistant cancer in asubject, the method comprising administering a therapeutically effectiveamount of the compound of claim 1, or a pharmaceutically acceptablesalt, solvate, or prodrug thereof, to the subject in need thereof. 49.The method of claim 44, wherein the cancer is triple negative breastcancer, high grade serous ovarian cancer, castration resistant prostatecancer, or doubly resistant prostate cancer.
 50. The method of claim 44,wherein the cancer is non-small cell lung cancer.
 51. The method ofclaim 44, further comprising administering one or more additionaltherapeutic agents to the subject.
 52. The method of claim 51, whereinthe one or more additional therapeutic agents are androgen receptorsignaling inhibitors.
 53. The method of claim 52, wherein the androgenreceptor signaling inhibitor is 3,3′-diindolylmethane (DIM), abirateroneacetate, ARN-509, bexlosteride, bicalutamide, dutasteride, epristeride,enzalutamide, finasteride, flutamide, izonsteride, ketoconazole,N-butylbenzene-sulfonamide, nilutamide, megestrol, steroidalantiandrogens, turosteride, or any combinations thereof. 54.-58.(canceled)